Location:
Triad Technology Center
333 Cassell Drive
Room 4400
Baltimore, MD 21224
Triad Technology Center
333 Cassell Drive
Room 4400
Baltimore, MD 21224
Phone: 443-740-2660
Email: mbaumann@mail.nih.gov
Background
Michael H. Baumann, PhD, is a Staff Scientist and Facility Head at the National Institute on Drug Abuse, Intramural Research Program, in Baltimore, MD. Dr. Baumann joined NIDA in 1991 as a Staff Fellow in the laboratory of Richard B. Rothman, MD, PhD. For more than twenty years, Drs. Baumann and Rothman examined the role of brain dopamine and serotonin systems in mediating the effects of therapeutic and abused stimulant drugs. In 2012, Dr. Baumann joined the laboratory of Amy H. Newman, PhD, where he established the Designer Drug Research Unit (DDRU). The main goal of the DDRU is to collect, analyze and disseminate the most up-to-date information about the pharmacology and toxicology of newly-emerging designer drugs of abuse, more formally known as new psychoactive substances (NPS). Working with partner organizations such as the Drug Enforcement Administration (DEA), the National Drug Early Warning System (NDEWS) and the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Dr. Baumann is kept informed about recent trends in the abuse of NPS. Most recently, his research team has characterized the molecular mechanism of action and biological effects for many of the so-called “bath salts” cathinones and their replacement analogs. DDRU scientists are now investigating the pharmacology of various NPS including synthetic cannabinoids, hallucinogens and opioids.
Publications
Selected Publications
2018 |
Elmore, Joshua S; Decker, Ann M; Sulima, Agnieszka; Rice, Kenner C; Partilla, John S; Blough, Bruce E; Baumann, Michael H Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats. Journal Article Neuropharmacology, 2018, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking). @article{Elmore:2018ab, title = {Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats.}, author = {Joshua S Elmore and Ann M Decker and Agnieszka Sulima and Kenner C Rice and John S Partilla and Bruce E Blough and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/29501528}, doi = {10.1016/j.neuropharm.2018.02.033}, issn = {1873-7064 (Electronic); 0028-3908 (Linking)}, year = {2018}, date = {2018-03-01}, journal = {Neuropharmacology}, address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.}, abstract = {2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3mg/kg), 25I-NBOMe (0.01-0.3mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0mg/kg) and DOI (0.03-1.0mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT2A antagonist (R)-(2,3-dimethoxyphenyl)1-[2-(4-fluorophenyl)ethyl]-4-piperidinylmethanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users.}, keywords = {}, pubstate = {published}, tppubtype = {article} } 2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3mg/kg), 25I-NBOMe (0.01-0.3mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0mg/kg) and DOI (0.03-1.0mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT2A antagonist (R)-(2,3-dimethoxyphenyl)1-[2-(4-fluorophenyl)ethyl]-4-piperidinylmethanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users. |
Elmore, Joshua S; Baumann, Michael H Repeated Exposure to the "Spice" Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats. Journal Article Front Psychiatry, 9 , pp. 55, 2018, ISSN: 1664-0640 (Print); 1664-0640 (Linking). @article{Elmore:2018aa, title = {Repeated Exposure to the "Spice" Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats.}, author = {Joshua S Elmore and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/29535650}, doi = {10.3389/fpsyt.2018.00055}, issn = {1664-0640 (Print); 1664-0640 (Linking)}, year = {2018}, date = {2018-02-27}, journal = {Front Psychiatry}, volume = {9}, pages = {55}, address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United States.}, abstract = {Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic compound found in psychoactive "spice" products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc) temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc) or its vehicle for seven consecutive days. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc) or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc), then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks), while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic compound found in psychoactive "spice" products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc) temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc) or its vehicle for seven consecutive days. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc) or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc), then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks), while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo. |
2017 |
Schindler, Charles W; Gramling, Benjamin R; Justinova, Zuzana; Thorndike, Eric B; Baumann, Michael H Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats. Journal Article Drug Alcohol Depend, 179 , pp. 387–394, 2017, ISSN: 1879-0046 (Electronic); 0376-8716 (Linking). @article{Schindler:2017aa, title = {Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats.}, author = {Charles W Schindler and Benjamin R Gramling and Zuzana Justinova and Eric B Thorndike and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/28846955}, doi = {10.1016/j.drugalcdep.2017.07.029}, issn = {1879-0046 (Electronic); 0376-8716 (Linking)}, year = {2017}, date = {2017-10-01}, journal = {Drug Alcohol Depend}, volume = {179}, pages = {387--394}, address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, United States; Preclinical Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, United States. Electronic address: cschind@helix.nih.gov.}, abstract = {BACKGROUND: The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Delta(9)-tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. METHODS: Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. RESULTS: THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the alpha1 adrenergic antagonist prazosin. CONCLUSIONS: Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Delta(9)-tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. METHODS: Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. RESULTS: THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the alpha1 adrenergic antagonist prazosin. CONCLUSIONS: Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow. |
Solis, Ernesto Jr; Partilla, John S; Sakloth, Farhana; Ruchala, Iwona; Schwienteck, Kathryn L; Felice, Louis De J; Eltit, Jose M; Glennon, Richard A; Negus, Stevens S; Baumann, Michael H N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability. Journal Article Neuropsychopharmacology, 42 (10), pp. 1950–1961, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking). @article{Solis:2017aa, title = {N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability.}, author = {Ernesto Jr Solis and John S Partilla and Farhana Sakloth and Iwona Ruchala and Kathryn L Schwienteck and Louis J De Felice and Jose M Eltit and Richard A Glennon and Stevens S Negus and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/28530234}, doi = {10.1038/npp.2017.98}, issn = {1740-634X (Electronic); 0893-133X (Linking)}, year = {2017}, date = {2017-09-01}, journal = {Neuropsychopharmacology}, volume = {42}, number = {10}, pages = {1950--1961}, address = {In Vivo Electrophysiology Unit, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.}, abstract = {Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds. |
Prekupec, Matthew P; Mansky, Peter A; Baumann, Michael H Misuse of Novel Synthetic Opioids: A Deadly New Trend. Journal Article J Addict Med, 11 (7), pp. 256–265, 2017. @article{Prekupec2017, title = {Misuse of Novel Synthetic Opioids: A Deadly New Trend. }, author = {Matthew P Prekupec and Peter A Mansky and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/28590391}, doi = {10.1097/ADM.0000000000000324}, year = {2017}, date = {2017-07-15}, journal = {J Addict Med}, volume = {11}, number = {7}, pages = {256--265}, abstract = {Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone. }, keywords = {}, pubstate = {published}, tppubtype = {article} } Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone. |
Elmore, Joshua S; Dillon-Carter, Ora; Partilla, John S; Ellefsen, Kayla N; Concheiro, Marta; Suzuki, Masaki; Rice, Kenner C; Huestis, Marilyn A; Baumann, Michael H Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats. Journal Article Neuropsychopharmacology, 42 (3), pp. 649–660, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking). @article{Elmore:2017aa, title = {Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats.}, author = {Joshua S Elmore and Ora Dillon-Carter and John S Partilla and Kayla N Ellefsen and Marta Concheiro and Masaki Suzuki and Kenner C Rice and Marilyn A Huestis and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/27658484}, doi = {10.1038/npp.2016.213}, issn = {1740-634X (Electronic); 0893-133X (Linking)}, year = {2017}, date = {2017-02-01}, journal = {Neuropsychopharmacology}, volume = {42}, number = {3}, pages = {649--660}, address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.}, abstract = {3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the beta-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (Tmax=15-45 min) and were short lived (t1/2=60-90 min), while HHMC and HMMC peaked later (Tmax=60-120 min) and persisted (t1/2=120-180 min). Area-under-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo.}, keywords = {}, pubstate = {published}, tppubtype = {article} } 3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the beta-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (Tmax=15-45 min) and were short lived (t1/2=60-90 min), while HHMC and HMMC peaked later (Tmax=60-120 min) and persisted (t1/2=120-180 min). Area-under-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo. |
2016 |
Schindler, Charles W; Thorndike, Eric B; Suzuki, Masaki; Rice, Kenner C; Baumann, Michael H Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-methylenedioxypyrovalerone (MDPV). Journal Article Br J Pharmacol, 173 (24), pp. 3492–3501, 2016, ISSN: 1476-5381 (Electronic); 0007-1188 (Linking). @article{Schindler:2016ab, title = {Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-methylenedioxypyrovalerone (MDPV).}, author = {Charles W Schindler and Eric B Thorndike and Masaki Suzuki and Kenner C Rice and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/27714779}, doi = {10.1111/bph.13640}, issn = {1476-5381 (Electronic); 0007-1188 (Linking)}, year = {2016}, date = {2016-12-01}, journal = {Br J Pharmacol}, volume = {173}, number = {24}, pages = {3492--3501}, address = {Preclinical Pharmacology Section, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD.}, abstract = {BACKGROUND AND PURPOSE: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here, we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats had telemetry transmitters surgically implanted for the measurement of BP and heart rate (HR). On test days, rats were placed individually in standard isolation cubicles. Following drug treatment, cardiovascular parameters were monitored for 3 h sessions. KEY RESULTS: Racemic MDPV (0.3-3.0 mg.kg(-1) ) increased BP and HR in a dose-dependent manner. The S(+) enantiomer (0.3-3.0 mg.kg(-1) ) of MDPV produced similar effects, while the R(-) enantiomer (0.3-3.0 mg.kg(-1) ) had no effects. Neither of the hydroxylated phase I metabolites of MDPV altered cardiovascular parameters significantly from baseline. Pretreatment with the ganglionic blocker chlorisondamine (1 and 3 mg.kg(-1) ) antagonized the increases in BP and HR produced by 1 mg.kg(-1) MDPV. The alpha1 -adrenoceptor antagonist prazosin (0.3 mg.kg(-1) ) attenuated the increase in BP following MDPV, while the beta-adrenoceptor antagonists propranolol (1 mg.kg(-1) ) and atenolol (1 and 3 mg.kg(-1) ) attenuated the HR increases. CONCLUSIONS AND IMPLICATIONS: The S(+) enantiomer appeared to mediate the cardiovascular effects of MDPV, while the metabolites of MDPV did not alter BP or HR significantly; MDPV increased BP and HR through activation of central sympathetic outflow. Mixed-action alpha/beta-adrenoceptor antagonists may be useful as treatments in counteracting the adverse cardiovascular effects of MDPV.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND AND PURPOSE: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here, we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats had telemetry transmitters surgically implanted for the measurement of BP and heart rate (HR). On test days, rats were placed individually in standard isolation cubicles. Following drug treatment, cardiovascular parameters were monitored for 3 h sessions. KEY RESULTS: Racemic MDPV (0.3-3.0 mg.kg(-1) ) increased BP and HR in a dose-dependent manner. The S(+) enantiomer (0.3-3.0 mg.kg(-1) ) of MDPV produced similar effects, while the R(-) enantiomer (0.3-3.0 mg.kg(-1) ) had no effects. Neither of the hydroxylated phase I metabolites of MDPV altered cardiovascular parameters significantly from baseline. Pretreatment with the ganglionic blocker chlorisondamine (1 and 3 mg.kg(-1) ) antagonized the increases in BP and HR produced by 1 mg.kg(-1) MDPV. The alpha1 -adrenoceptor antagonist prazosin (0.3 mg.kg(-1) ) attenuated the increase in BP following MDPV, while the beta-adrenoceptor antagonists propranolol (1 mg.kg(-1) ) and atenolol (1 and 3 mg.kg(-1) ) attenuated the HR increases. CONCLUSIONS AND IMPLICATIONS: The S(+) enantiomer appeared to mediate the cardiovascular effects of MDPV, while the metabolites of MDPV did not alter BP or HR significantly; MDPV increased BP and HR through activation of central sympathetic outflow. Mixed-action alpha/beta-adrenoceptor antagonists may be useful as treatments in counteracting the adverse cardiovascular effects of MDPV. |
Mayer, F P; Wimmer, L; Dillon-Carter, O; Partilla, J S; Burchardt, N V; Mihovilovic, M D; Baumann, M H; Sitte, H H Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters. Journal Article Br J Pharmacol, 173 (17), pp. 2657–2668, 2016, ISSN: 1476-5381 (Electronic); 0007-1188 (Linking). @article{Mayer:2016aa, title = {Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters.}, author = {F P Mayer and L Wimmer and O Dillon-Carter and J S Partilla and N V Burchardt and M D Mihovilovic and M H Baumann and H H Sitte}, url = {https://www.ncbi.nlm.nih.gov/pubmed/27391165}, doi = {10.1111/bph.13547}, issn = {1476-5381 (Electronic); 0007-1188 (Linking)}, year = {2016}, date = {2016-09-01}, journal = {Br J Pharmacol}, volume = {173}, number = {17}, pages = {2657--2668}, address = {Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.}, abstract = {BACKGROUND AND PURPOSE: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. EXPERIMENTAL APPROACH: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg.kg(-1) ) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. KEY RESULTS: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood-brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND AND PURPOSE: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. EXPERIMENTAL APPROACH: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg.kg(-1) ) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. KEY RESULTS: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood-brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone. |
Schindler, Charles W; Thorndike, Eric B; Goldberg, Steven R; Lehner, Kurt R; Cozzi, Nicholas V; Brandt, Simon D; Baumann, Michael H Psychopharmacology (Berl), 233 (10), pp. 1981–1990, 2016, ISSN: 1432-2072 (Electronic); 0033-3158 (Linking). @article{Schindler:2016aa, title = {Reinforcing and neurochemical effects of the "bath salts" constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats.}, author = {Charles W Schindler and Eric B Thorndike and Steven R Goldberg and Kurt R Lehner and Nicholas V Cozzi and Simon D Brandt and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26319160}, doi = {10.1007/s00213-015-4057-0}, issn = {1432-2072 (Electronic); 0033-3158 (Linking)}, year = {2016}, date = {2016-05-01}, journal = {Psychopharmacology (Berl)}, volume = {233}, number = {10}, pages = {1981--1990}, address = {Preclinical Pharmacology Section, Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. cschind@helix.nih.gov.}, abstract = {RATIONALE: 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called "bath salts" products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT). OBJECTIVES: We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. METHODS: To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. RESULTS: MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. In contrast, methylone self-administration (0.3 and 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. CONCLUSIONS: Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats, suggesting these drugs possess significant abuse liability in humans.}, keywords = {}, pubstate = {published}, tppubtype = {article} } RATIONALE: 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called "bath salts" products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT). OBJECTIVES: We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. METHODS: To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. RESULTS: MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. In contrast, methylone self-administration (0.3 and 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. CONCLUSIONS: Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats, suggesting these drugs possess significant abuse liability in humans. |
Marusich, Julie A; Antonazzo, Kateland R; Blough, Bruce E; Brandt, Simon D; Kavanagh, Pierce V; Partilla, John S; Baumann, Michael H Neuropharmacology, 101 , pp. 68–75, 2016, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking). @article{Marusich:2016aa, title = {The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue.}, author = {Julie A Marusich and Kateland R Antonazzo and Bruce E Blough and Simon D Brandt and Pierce V Kavanagh and John S Partilla and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26362361}, doi = {10.1016/j.neuropharm.2015.09.004}, issn = {1873-7064 (Electronic); 0028-3908 (Linking)}, year = {2016}, date = {2016-02-01}, journal = {Neuropharmacology}, volume = {101}, pages = {68--75}, address = {Center for Drug Discovery, RTI International, 3040 Cornwallis Rd, Research Triangle Park, NC 27709, USA. Electronic address: jmarusich@rti.org.}, abstract = {In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users. |
2015 |
Kolanos, R; Sakloth, F; Jain, A D; Partilla, J S; Baumann, M H; Glennon, R A Structural Modification of the Designer Stimulant alpha-Pyrrolidinovalerophenone (alpha-PVP) Influences Potency at Dopamine Transporters. Journal Article ACS Chem Neurosci, 6 (10), pp. 1726–1731, 2015, ISSN: 1948-7193 (Electronic); 1948-7193 (Linking). @article{Kolanos:2015aa, title = {Structural Modification of the Designer Stimulant alpha-Pyrrolidinovalerophenone (alpha-PVP) Influences Potency at Dopamine Transporters.}, author = {R Kolanos and F Sakloth and A D Jain and J S Partilla and M H Baumann and R A Glennon}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26217965}, doi = {10.1021/acschemneuro.5b00160}, issn = {1948-7193 (Electronic); 1948-7193 (Linking)}, year = {2015}, date = {2015-10-21}, journal = {ACS Chem Neurosci}, volume = {6}, number = {10}, pages = {1726--1731}, address = {Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , 800 East Leigh Street, PO Box 980540, Richmond, Virginia 23298, United States.}, abstract = {alpha-Pyrrolidinovalerophenone (alpha-PVP, 7) is an illegal synthetic stimulant that is being sold on the clandestine market as "flakka" and "gravel". The potent pharmacological effects of alpha-PVP are presumably mediated by inhibition of dopamine uptake at the dopamine transporter (DAT). However, little is known about how structural modification of alpha-PVP influences activity at DAT. Eleven analogs of alpha-PVP were synthesized and examined for their ability to inhibit uptake of [(3)H]dopamine and [(3)H]serotonin in rat brain synaptosomes. None of the analogs significantly inhibited [(3)H]serotonin uptake when tested at 10 muM at the serotonin transporter (SERT). All of the analogs behaved as DAT reuptake inhibitors, but potencies varied over a >1500-fold range. Potency was primarily associated with the nature of the alpha-substituent, with the more bulky substituents imparting the highest potency. Expansion of the pyrrolidine ring to a piperidine reduced potency up to 10-fold, whereas conformational constraint in the form of an aminotetralone resulted in the least potent compound. Our study provides the first systematic and comparative structure-activity investigation on the ability of alpha-PVP analogs to act as inhibitors of DAT.}, keywords = {}, pubstate = {published}, tppubtype = {article} } alpha-Pyrrolidinovalerophenone (alpha-PVP, 7) is an illegal synthetic stimulant that is being sold on the clandestine market as "flakka" and "gravel". The potent pharmacological effects of alpha-PVP are presumably mediated by inhibition of dopamine uptake at the dopamine transporter (DAT). However, little is known about how structural modification of alpha-PVP influences activity at DAT. Eleven analogs of alpha-PVP were synthesized and examined for their ability to inhibit uptake of [(3)H]dopamine and [(3)H]serotonin in rat brain synaptosomes. None of the analogs significantly inhibited [(3)H]serotonin uptake when tested at 10 muM at the serotonin transporter (SERT). All of the analogs behaved as DAT reuptake inhibitors, but potencies varied over a >1500-fold range. Potency was primarily associated with the nature of the alpha-substituent, with the more bulky substituents imparting the highest potency. Expansion of the pyrrolidine ring to a piperidine reduced potency up to 10-fold, whereas conformational constraint in the form of an aminotetralone resulted in the least potent compound. Our study provides the first systematic and comparative structure-activity investigation on the ability of alpha-PVP analogs to act as inhibitors of DAT. |
Baumann, Michael H; Volkow, Nora D Abuse of New Psychoactive Substances: Threats and Solutions. Journal Article Neuropsychopharmacology, 41 (3), pp. 663–665, 2015, ISSN: 1740-634X (Electronic); 0893-133X (Linking). @article{Baumann:2016aa, title = {Abuse of New Psychoactive Substances: Threats and Solutions.}, author = {Michael H Baumann and Nora D Volkow}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26303285}, doi = {10.1038/npp.2015.260}, issn = {1740-634X (Electronic); 0893-133X (Linking)}, year = {2015}, date = {2015-08-25}, journal = {Neuropsychopharmacology}, volume = {41}, number = {3}, pages = {663--665}, address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Rothman, Richard B; Ananthan, Subramaniam; Partilla, John S; Saini, Surendra K; Moukha-Chafiq, Omar; Pathak, Vibha; Baumann, Michael H Studies of the biogenic amine transporters 15. Identification of novel allosteric dopamine transporter ligands with nanomolar potency. Journal Article J Pharmacol Exp Ther, 353 (3), pp. 529–538, 2015. @article{Rothman2015, title = {Studies of the biogenic amine transporters 15. Identification of novel allosteric dopamine transporter ligands with nanomolar potency.}, author = {Richard B Rothman and Subramaniam Ananthan and John S Partilla and Surendra K Saini and Omar Moukha-Chafiq and Vibha Pathak and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/25788711}, doi = {10.1124/jpet.114.222299}, year = {2015}, date = {2015-06-01}, journal = {J Pharmacol Exp Ther}, volume = {353}, number = {3}, pages = {529--538}, abstract = {Novel allosteric modulators of the dopamine transporter (DAT) have been identified. We have shown previously that SRI-9804 [N-(diphenylmethyl)-2-phenyl-4-quinazolinamine], SRI-20040 [N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine], and SRI-20041 [N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine] partially inhibit [(125)I]RTI-55 ([(125)I]3β-(4'-iodophenyl)tropan-2β-carboxylic acid methyl ester) binding and [(3)H]dopamine ([(3)H]DA) uptake, slow the dissociation rate of [(125)I]RTI-55 from the DAT, and allosterically modulate d-amphetamine-induced, DAT-mediated DA release. We synthesized and evaluated the activity of >500 analogs of these ligands and report here on 36 selected compounds. Using synaptosomes prepared from rat caudate, we conducted [(3)H]DA uptake inhibition assays, DAT binding assays with [(3)H]WIN35428 ([(3)H]2β-carbomethoxy-3β-(4-fluorophenyl)tropane), and DAT-mediated release assays with either [(3)H]MPP(+) ([(3)H]1-methyl-4-phenylpyridinium) or [(3)H]DA. We observed three groups of [(3)H]DA uptake inhibitors: 1) full-efficacy agents with a one-site fit, 2) full-efficacy agents with a two-site fit, and 3) partial-efficacy agents with a one-site fit-the focus of further studies. These agents partially inhibited DA, serotonin, and norepinephrine uptake, yet were much less potent at inhibiting [(3)H]WIN35428 binding to the DAT. For example, SRI-29574 [N-(2,2-diphenylethyl)-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine] partially inhibited DAT uptake, with an IC50 = 2.3 ± 0.4 nM, without affecting binding to the DAT. These agents did not alter DAT-mediated release of [(3)H]MPP(+) in the absence or presence of 100 nM d-amphetamine. SRI-29574 had no significant effect on the d-amphetamine EC50 or Emax value for DAT-mediated release of [(3)H]MPP(+). These studies demonstrate the existence of potent DAT ligands that partially block [(3)H]DA uptake, without affecting DAT binding or d-amphetamine-induced [(3)H]MPP(+) release. These compounds may prove to be useful probes of biogenic amine transporter function as well as novel therapeutics.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Novel allosteric modulators of the dopamine transporter (DAT) have been identified. We have shown previously that SRI-9804 [N-(diphenylmethyl)-2-phenyl-4-quinazolinamine], SRI-20040 [N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine], and SRI-20041 [N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine] partially inhibit [(125)I]RTI-55 ([(125)I]3β-(4'-iodophenyl)tropan-2β-carboxylic acid methyl ester) binding and [(3)H]dopamine ([(3)H]DA) uptake, slow the dissociation rate of [(125)I]RTI-55 from the DAT, and allosterically modulate d-amphetamine-induced, DAT-mediated DA release. We synthesized and evaluated the activity of >500 analogs of these ligands and report here on 36 selected compounds. Using synaptosomes prepared from rat caudate, we conducted [(3)H]DA uptake inhibition assays, DAT binding assays with [(3)H]WIN35428 ([(3)H]2β-carbomethoxy-3β-(4-fluorophenyl)tropane), and DAT-mediated release assays with either [(3)H]MPP(+) ([(3)H]1-methyl-4-phenylpyridinium) or [(3)H]DA. We observed three groups of [(3)H]DA uptake inhibitors: 1) full-efficacy agents with a one-site fit, 2) full-efficacy agents with a two-site fit, and 3) partial-efficacy agents with a one-site fit-the focus of further studies. These agents partially inhibited DA, serotonin, and norepinephrine uptake, yet were much less potent at inhibiting [(3)H]WIN35428 binding to the DAT. For example, SRI-29574 [N-(2,2-diphenylethyl)-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine] partially inhibited DAT uptake, with an IC50 = 2.3 ± 0.4 nM, without affecting binding to the DAT. These agents did not alter DAT-mediated release of [(3)H]MPP(+) in the absence or presence of 100 nM d-amphetamine. SRI-29574 had no significant effect on the d-amphetamine EC50 or Emax value for DAT-mediated release of [(3)H]MPP(+). These studies demonstrate the existence of potent DAT ligands that partially block [(3)H]DA uptake, without affecting DAT binding or d-amphetamine-induced [(3)H]MPP(+) release. These compounds may prove to be useful probes of biogenic amine transporter function as well as novel therapeutics. |
Saha, Kusumika; Partilla, John S; Lehner, Kurt R; Seddik, Amir; Stockner, Thomas; Holy, Marion; Sandtner, Walter; Ecker, Gerhard F; Sitte, Harald H; Baumann, Michael H 'Second-generation' mephedrone analogs, 4-MEC and 4-MePPP, differentially affect monoamine transporter function. Journal Article Neuropsychopharmacology, 40 (6), pp. 1321–1331, 2015, ISSN: 1740-634X (Electronic); 0893-133X (Linking). @article{Saha:2015aa, title = {'Second-generation' mephedrone analogs, 4-MEC and 4-MePPP, differentially affect monoamine transporter function.}, author = {Kusumika Saha and John S Partilla and Kurt R Lehner and Amir Seddik and Thomas Stockner and Marion Holy and Walter Sandtner and Gerhard F Ecker and Harald H Sitte and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/25502630}, doi = {10.1038/npp.2014.325}, issn = {1740-634X (Electronic); 0893-133X (Linking)}, year = {2015}, date = {2015-05-01}, journal = {Neuropsychopharmacology}, volume = {40}, number = {6}, pages = {1321--1331}, address = {Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.}, abstract = {The nonmedical use of synthetic cathinones is increasing on a global scale. 4-Methyl-N-methylcathinone (mephedrone) is a popular synthetic cathinone that is now illegal in the United States and other countries. Since the legislative ban on mephedrone, a number of 'second-generation' analogs have appeared in the street drug marketplace, including 4-methyl-N-ethylcathinone (4-MEC) and 4'-methyl-alpha-pyrrolidinopropiophenone (4-MePPP). Here we characterized the interactions of 4-MEC and 4-MePPP with transporters for 5-HT (SERT) and dopamine (DAT) using molecular, cellular, and whole-animal methods. In vitro transporter assays revealed that 4-MEC displays unusual 'hybrid' activity as a SERT substrate (ie, 5-HT releaser) and DAT blocker, whereas 4-MePPP is a blocker at both transporters but more potent at DAT. In vivo microdialysis experiments in rat brain demonstrated that 4-MEC (1-3 mg/kg, i.v.) produced large increases in extracellular 5-HT, small increases in dopamine, and minimal motor stimulation. In contrast, 4-MePPP (1-3 mg/kg, i.v.) produced selective increases in dopamine and robust motor stimulation. Consistent with its activity as a SERT substrate, 4-MEC evoked inward current in SERT-expressing Xenopus oocytes, whereas 4-MePPP was inactive in this regard. To examine drug-transporter interactions at the molecular level, we modeled the fit of 4-MEC and 4-MePPP into the binding pockets for DAT and SERT. Subtle distinctions in ligand-transporter binding were found that account for the differential effects of 4-MEC and 4-MePPP at SERT. Collectively, our results provide key information about the pharmacology of newly emerging mephedrone analogs, and give clues to structural requirements that govern drug selectivity at DAT vs SERT.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The nonmedical use of synthetic cathinones is increasing on a global scale. 4-Methyl-N-methylcathinone (mephedrone) is a popular synthetic cathinone that is now illegal in the United States and other countries. Since the legislative ban on mephedrone, a number of 'second-generation' analogs have appeared in the street drug marketplace, including 4-methyl-N-ethylcathinone (4-MEC) and 4'-methyl-alpha-pyrrolidinopropiophenone (4-MePPP). Here we characterized the interactions of 4-MEC and 4-MePPP with transporters for 5-HT (SERT) and dopamine (DAT) using molecular, cellular, and whole-animal methods. In vitro transporter assays revealed that 4-MEC displays unusual 'hybrid' activity as a SERT substrate (ie, 5-HT releaser) and DAT blocker, whereas 4-MePPP is a blocker at both transporters but more potent at DAT. In vivo microdialysis experiments in rat brain demonstrated that 4-MEC (1-3 mg/kg, i.v.) produced large increases in extracellular 5-HT, small increases in dopamine, and minimal motor stimulation. In contrast, 4-MePPP (1-3 mg/kg, i.v.) produced selective increases in dopamine and robust motor stimulation. Consistent with its activity as a SERT substrate, 4-MEC evoked inward current in SERT-expressing Xenopus oocytes, whereas 4-MePPP was inactive in this regard. To examine drug-transporter interactions at the molecular level, we modeled the fit of 4-MEC and 4-MePPP into the binding pockets for DAT and SERT. Subtle distinctions in ligand-transporter binding were found that account for the differential effects of 4-MEC and 4-MePPP at SERT. Collectively, our results provide key information about the pharmacology of newly emerging mephedrone analogs, and give clues to structural requirements that govern drug selectivity at DAT vs SERT. |
2014 |
Marusich, Julie A; Antonazzo, Kateland R; Wiley, Jenny L; Blough, Bruce E; Partilla, John S; Baumann, Michael H Pharmacology of novel synthetic stimulants structurally related to the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV). Journal Article Neuropharmacology, 87 , pp. 206–213, 2014, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking). @article{Marusich:2014aa, title = {Pharmacology of novel synthetic stimulants structurally related to the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV).}, author = {Julie A Marusich and Kateland R Antonazzo and Jenny L Wiley and Bruce E Blough and John S Partilla and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/24594476}, doi = {10.1016/j.neuropharm.2014.02.016}, issn = {1873-7064 (Electronic); 0028-3908 (Linking)}, year = {2014}, date = {2014-12-01}, journal = {Neuropharmacology}, volume = {87}, pages = {206--213}, address = {RTI International, 3040 Cornwallis Rd., Research Triangle Park, NC 27709, USA. Electronic address: jmarusich@rti.org.}, abstract = {There has been a dramatic rise in the abuse of synthetic cathinones known as "bath salts," including 3,4-methylenedioxypyrovalerone (MDPV), an analog linked to many adverse events. MDPV differs from other synthetic cathinones because it contains a pyrrolidine ring which gives the drug potent actions as an uptake blocker at dopamine and norepinephrine transporters. While MDPV is now illegal, a wave of "second generation" pyrrolidinophenones has appeared on the market, with alpha-pyrrolidinovalerophenone (alpha-PVP) being most popular. Here, we sought to compare the in vitro and in vivo pharmacological effects of MDPV and its congeners: alpha-PVP, alpha-pyrrolidinobutiophenone (alpha-PBP), and alpha-pyrrolidinopropiophenone (alpha-PPP). We examined effects of test drugs in transporter uptake and release assays using rat brain synaptosomes, then assessed behavioral stimulant effects in mice. We found that alpha-PVP is a potent uptake blocker at dopamine and norepinephrine transporters, similar to MDPV. alpha-PBP and alpha-PPP are also catecholamine transporter blockers but display reduced potency. All of the test drugs are locomotor stimulants, and the rank order of in vivo potency parallels dopamine transporter activity, with MDPV > alpha-PVP > alpha-PBP > alpha-PPP. Motor activation produced by all drugs is reversed by the dopamine receptor antagonist SCH23390. Furthermore, results of a functional observational battery show that all test drugs produce typical stimulant effects at lower doses and some drugs produce bizarre behaviors at higher doses. Taken together, our findings represent the first evidence that second generation analogs of MDPV are catecholamine-selective uptake blockers which may pose risk for addiction and adverse effects in human users. This article is part of the Special Issue entitled 'CNS Stimulants'.}, keywords = {}, pubstate = {published}, tppubtype = {article} } There has been a dramatic rise in the abuse of synthetic cathinones known as "bath salts," including 3,4-methylenedioxypyrovalerone (MDPV), an analog linked to many adverse events. MDPV differs from other synthetic cathinones because it contains a pyrrolidine ring which gives the drug potent actions as an uptake blocker at dopamine and norepinephrine transporters. While MDPV is now illegal, a wave of "second generation" pyrrolidinophenones has appeared on the market, with alpha-pyrrolidinovalerophenone (alpha-PVP) being most popular. Here, we sought to compare the in vitro and in vivo pharmacological effects of MDPV and its congeners: alpha-PVP, alpha-pyrrolidinobutiophenone (alpha-PBP), and alpha-pyrrolidinopropiophenone (alpha-PPP). We examined effects of test drugs in transporter uptake and release assays using rat brain synaptosomes, then assessed behavioral stimulant effects in mice. We found that alpha-PVP is a potent uptake blocker at dopamine and norepinephrine transporters, similar to MDPV. alpha-PBP and alpha-PPP are also catecholamine transporter blockers but display reduced potency. All of the test drugs are locomotor stimulants, and the rank order of in vivo potency parallels dopamine transporter activity, with MDPV > alpha-PVP > alpha-PBP > alpha-PPP. Motor activation produced by all drugs is reversed by the dopamine receptor antagonist SCH23390. Furthermore, results of a functional observational battery show that all test drugs produce typical stimulant effects at lower doses and some drugs produce bizarre behaviors at higher doses. Taken together, our findings represent the first evidence that second generation analogs of MDPV are catecholamine-selective uptake blockers which may pose risk for addiction and adverse effects in human users. This article is part of the Special Issue entitled 'CNS Stimulants'. |
Baumann, Michael H; Solis, Ernesto Jr; Watterson, Lucas R; Marusich, Julie A; Fantegrossi, William E; Wiley, Jenny L Baths salts, spice, and related designer drugs: the science behind the headlines. Journal Article J Neurosci, 34 (46), pp. 15150–15158, 2014, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking). @article{Baumann:2014aa, title = {Baths salts, spice, and related designer drugs: the science behind the headlines.}, author = {Michael H Baumann and Ernesto Jr Solis and Lucas R Watterson and Julie A Marusich and William E Fantegrossi and Jenny L Wiley}, url = {https://www.ncbi.nlm.nih.gov/pubmed/25392483}, doi = {10.1523/JNEUROSCI.3223-14.2014}, issn = {1529-2401 (Electronic); 0270-6474 (Linking)}, year = {2014}, date = {2014-11-12}, journal = {J Neurosci}, volume = {34}, number = {46}, pages = {15150--15158}, address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, mbaumann@mail.nih.gov.}, abstract = {The abuse of synthetic psychoactive substances known as "designer drugs," or "new psychoactive substances" (NPS), is increasing at an alarming rate. NPS are purchased as alternatives to traditional illicit drugs of abuse and are manufactured to circumvent laws regulating the sale and use of controlled substances. Synthetic cathinones (i.e., "bath salts") and synthetic cannabinoids (i.e., "spice") are two types of NPS that have received substantial media attention. Although low recreational doses of bath salts or spice compounds can produce desirable effects, high doses or chronic exposure often leads to dangerous medical consequences, including psychosis, violent behaviors, tachycardia, hyperthermia, and even death. Despite the popularity of NPS, there is a paucity of scientific data about these drugs. Here we provide a brief up-to-date review describing the mechanisms of action and neurobiological effects of synthetic cathinones and cannabinoids.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The abuse of synthetic psychoactive substances known as "designer drugs," or "new psychoactive substances" (NPS), is increasing at an alarming rate. NPS are purchased as alternatives to traditional illicit drugs of abuse and are manufactured to circumvent laws regulating the sale and use of controlled substances. Synthetic cathinones (i.e., "bath salts") and synthetic cannabinoids (i.e., "spice") are two types of NPS that have received substantial media attention. Although low recreational doses of bath salts or spice compounds can produce desirable effects, high doses or chronic exposure often leads to dangerous medical consequences, including psychosis, violent behaviors, tachycardia, hyperthermia, and even death. Despite the popularity of NPS, there is a paucity of scientific data about these drugs. Here we provide a brief up-to-date review describing the mechanisms of action and neurobiological effects of synthetic cathinones and cannabinoids. |
Schindler, Charles W; Thorndike, Eric B; Blough, Bruce E; Tella, Srihari R; Goldberg, Steven R; Baumann, Michael H Effects of 3,4-methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats. Journal Article Br J Pharmacol, 171 (1), pp. 83–91, 2014, ISSN: 1476-5381 (Electronic); 0007-1188 (Linking). @article{Schindler:2014aa, title = {Effects of 3,4-methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats.}, author = {Charles W Schindler and Eric B Thorndike and Bruce E Blough and Srihari R Tella and Steven R Goldberg and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/24328722}, doi = {10.1111/bph.12423}, issn = {1476-5381 (Electronic); 0007-1188 (Linking)}, year = {2014}, date = {2014-01-01}, journal = {Br J Pharmacol}, volume = {171}, number = {1}, pages = {83--91}, address = {Preclinical Pharmacology, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.}, abstract = {BACKGROUND AND PURPOSE: The cardiovascular effects produced by 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats. EXPERIMENTAL APPROACH: Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP, heart rate (HR) and locomotor activity in conscious male rats. KEY RESULTS: MDMA (1-20 mg.kg(-1)) produced dose-related increases in BP, HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N-demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA. The metabolite 3,4-dihydroxymethamphetamine (HHMA; 1-10 mg.kg(-1)) increased HR more potently and to a greater extent than MDMA, whereas 3,4-dihydroxyamphetamine (HHA) increased HR, but to a lesser extent than HHMA. Neither dihydroxy metabolite altered motor activity. The metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA) and 4-hydroxy-3-methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the beta-adrenoceptor antagonist propranolol. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo. As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND AND PURPOSE: The cardiovascular effects produced by 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats. EXPERIMENTAL APPROACH: Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP, heart rate (HR) and locomotor activity in conscious male rats. KEY RESULTS: MDMA (1-20 mg.kg(-1)) produced dose-related increases in BP, HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N-demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA. The metabolite 3,4-dihydroxymethamphetamine (HHMA; 1-10 mg.kg(-1)) increased HR more potently and to a greater extent than MDMA, whereas 3,4-dihydroxyamphetamine (HHA) increased HR, but to a lesser extent than HHMA. Neither dihydroxy metabolite altered motor activity. The metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA) and 4-hydroxy-3-methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the beta-adrenoceptor antagonist propranolol. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo. As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study. |
2013 |
Schindler, Charles W; Thorndike, Eric B; Blough, Bruce E; Tella, Srihari R; Goldberg, Steven R; Baumann, Michael H Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA) and its pharmacodynamic consequences in the rat. ( Journal Article Drug Metab Dispos, 42 (1), pp. 119–125, 2013. @article{Schindler2018, title = {Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA) and its pharmacodynamic consequences in the rat. (}, author = {Charles W Schindler and Eric B Thorndike and Bruce E Blough and Srihari R Tella and Steven R Goldberg and Michael H Baumann}, url = {https://www.ncbi.nlm.nih.gov/pubmed/24141857}, doi = {10.1124/dmd.113.053678}, year = {2013}, date = {2013-10-18}, journal = {Drug Metab Dispos}, volume = {42}, number = {1}, pages = {119--125}, abstract = {3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug that can cause severe and even fatal adverse effects. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. Preclinical studies to determine MDMA's safety are needed. We evaluated MDMA's pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mg/kg s.c. MDMA, and the associated pharmacodynamic consequences. Blood was collected via jugular catheter at 0, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours, with simultaneous serotonin (5-HT) behavioral syndrome and core temperature monitoring. Plasma specimens were analyzed for MDMA and the metabolites (+/-)-3,4-dihydroxymethamphetamine (HHMA), (+/-)-4-hydroxy-3-methoxymethamphetamine (HMMA), and (+/-)-3,4-methylenedioxyamphetamine (MDA) by liquid chromatography-tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA Cmax was 164 +/- 47.1 ng/ml, HHMA and HMMA were major metabolites, and <20% of MDMA was metabolized to MDA. After 5- and 10-mg/kg doses, MDMA areas under the curve (AUCs) were 3- and 10-fold greater than those after 2.5 mg/kg; HHMA and HMMA AUC values were relatively constant across doses; and MDA AUC values were greater than dose-proportional. Our data provide decisive in vivo evidence that MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in the rat. Importantly, 5-HT syndrome severity correlated with MDMA concentrations (r = 0.8083; P < 0.0001) and core temperature correlated with MDA concentrations (r = 0.7595; P < 0.0001), suggesting that MDMA's behavioral and hyperthermic effects may involve distinct mechanisms. Given key similarities between MDMA pharmacokinetics in rats and humans, data from rats can be useful when provided at clinically relevant doses.}, keywords = {}, pubstate = {published}, tppubtype = {article} } 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug that can cause severe and even fatal adverse effects. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. Preclinical studies to determine MDMA's safety are needed. We evaluated MDMA's pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mg/kg s.c. MDMA, and the associated pharmacodynamic consequences. Blood was collected via jugular catheter at 0, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours, with simultaneous serotonin (5-HT) behavioral syndrome and core temperature monitoring. Plasma specimens were analyzed for MDMA and the metabolites (+/-)-3,4-dihydroxymethamphetamine (HHMA), (+/-)-4-hydroxy-3-methoxymethamphetamine (HMMA), and (+/-)-3,4-methylenedioxyamphetamine (MDA) by liquid chromatography-tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA Cmax was 164 +/- 47.1 ng/ml, HHMA and HMMA were major metabolites, and <20% of MDMA was metabolized to MDA. After 5- and 10-mg/kg doses, MDMA areas under the curve (AUCs) were 3- and 10-fold greater than those after 2.5 mg/kg; HHMA and HMMA AUC values were relatively constant across doses; and MDA AUC values were greater than dose-proportional. Our data provide decisive in vivo evidence that MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in the rat. Importantly, 5-HT syndrome severity correlated with MDMA concentrations (r = 0.8083; P < 0.0001) and core temperature correlated with MDA concentrations (r = 0.7595; P < 0.0001), suggesting that MDMA's behavioral and hyperthermic effects may involve distinct mechanisms. Given key similarities between MDMA pharmacokinetics in rats and humans, data from rats can be useful when provided at clinically relevant doses. |
