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Richard A. Glennon - One of the best experts on this subject based on the ideXlab platform.
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Systematic Structure–Activity Studies on Selected 2‑, 3‑, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents
2018Co-Authors: Donna Walther, Michael H Baumann, Abdelrahman R. Shalabi, Richard A. GlennonAbstract:Methcathinone analogs are appearing on the clandestine market at a rate nearly out-pacing the ability of investigators to examine them on an individual basis. To formulate structure–activity relationship (SAR) generalities, we examined the releasing ability of several simple Methcathinone analogs at the three monoamine transporters (i.e., the dopamine, norepinephrine, and serotonin transporters, DAT, NET, and SERT, respectively) using in vitro assay methods. The analogs included Methcathinone and 14 other compounds monosubstituted at the 2-, 3-, or 4-position. In general, (a) the 2-substituted analogs were less potent than either the 3- or 4-substituted analogs, (b) the 3- and 4-substituted analogs were relatively similar in potency, (c) Methcathinone was the most selective as a DAT-releasing agent, and (d) the 3- and 4-CF3 analogs were the least DAT-selective. For the 15 compounds, there was a significant correlation (r > 0.9) between DAT and NET potency, suggesting relatively similar structure–activity relationships (at least for the compounds examined here). Several of the compounds have appeared on the clandestine market since our studies were initiated, and the present results provide new information on how they might act
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quantitative structure activity relationship analysis of the pharmacology of para substituted Methcathinone analogues
British Journal of Pharmacology, 2015Co-Authors: Julie S Bonano, Nicholas V Cozzi, Richard A. Glennon, John S Partilla, Matthew L Banks, Renata Kolanos, Farhana Sakloth, M L Barnier, Michael H Baumann, S S NegusAbstract:Background and Purpose Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure–activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es), electronic (σp) and lipophilic (πp) parameters of the para substituents. Experimental Approach For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation. Key Results MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation. Conclusions and Implications Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es) are key determinants of this selectivity.
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in vitro characterization of ephedrine related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Richard B Rothman, Richard Young, John S Partilla, Bryan L Roth, Sandra J Hufeisen, Beth Ann Comptontoth, Jon Birkes, Richard A. GlennonAbstract:Ephedrine is a long-studied stimulant available both as a prescription and over-the-counter medication, as well as an ingredient in widely marketed herbal preparations, and is also used as a precursor for the illicit synthesis of methamphetamine. Ephedrine is related to phenylpropanolamine, a decongestant removed from the market place due to concerns that its use increased the risk of hemorrhagic stroke. Standard pharmacology texts emphasize that ephedrine is both a direct and indirect adrenergic agonist, activating adrenergic receptors both by direct agonist activity as well as by releasing norepinephrine via a carrier-mediated exchange mechanism. Chemically, ephedrine possesses two chiral centers. In the present study, we characterized the stereoisomers of ephedrine and the closely related compounds pseudoephedrine, norephedrine, pseudonorephedrine (cathine), Methcathinone, and cathinone at biogenic amine transporters and a large battery of cloned human receptors (e.g., “receptorome”). The most potent actions of ephedrine-type compounds were as substrates of the norepinephrine transporter (EC 50 values of about 50 nM) followed by substrate activity at the dopamine transporter. Screening the receptorome demonstrated weak affinity at α 2 -adrenergic and 5-hydroxytryptamine 7 receptors ( K i values 1–10 μM) and no significant activity at β-adrenergic or α 1 -adrenergic receptors. Viewed collectively, these data indicate that the pharmacological effects of ephedrine-like phenylpropanolamines are likely mediated by norepinephrine release, and although sharing mechanistic similarities with, they differ in important respects from those of the phenylpropanonamines Methcathinone and cathinone and the phenyisopropylamines methamphetamine and amphetamine.
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Cathinone: An Investigation of Several N -Alkyl and Methylenedioxy-Substituted Analogs
Pharmacology biochemistry and behavior, 1997Co-Authors: Terry A. Dal Cason, Richard Young, Richard A. GlennonAbstract:DAL CASON, T. A., R. YOUNG AND R. A. GLENNON. Cathinone: An investigation of several N-alkyl and methylenedioxy-substituted analogs. PHARMACOL BIOCHEM BEHAV 58(4) 1109–1116, 1997.—Structurally, Methcathinone is to cathinone what methamphetamine is to amphetamine. Due to increased interest in the abuse of such agents we wished to determine if certain derivatives of cathinone would behave in a manner consistent with what is known about their amphetamine counterparts; that is, can amphetamine structure–activity relationships be extrapolated to cathinone analogs? As expected on the basis of known structure–activity relationships for amphetaminergic agents, both N-monoethylcathinone and N-mono-n-propylcathinone (N-Et CAT and N-Pr CAT; ED50 = 0.77 and 2.03 mg/kg, respectively) produced amphetamine-like stimulus effects in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle and were somewhat less potent than racemic Methcathinone. In contrast, (−)N,N-dimethylcathinone or (−)Di Me CAT (ED50 = 0.44 mg/kg) was more potent than expected; although (+)N,N-dimethylamphetamine is sevenfold less potent than (+)methamphetamine, (−)Di Me CAT is only about 1.6-fold less potent than (−)Methcathinone, and is essentially equipotent with (−)cathinone. In addition, although it has been previously demonstrated that 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) results in stimulus generalization in rats trained to discriminate (+)amphetamine or DOM from vehicle, the cathinone counterpart of MDA (i.e., MDC) resulted in partial (maximum: 58%) generalization in (+)amphetamine-trained animals, and failed to produce >7% DOM-appropriate responding in rats trained to discriminate DOM from vehicle. On the other hand, the N-methyl analog of MDC (i.e., MDMC) behaved in a manner similar to that of the N-methyl analog of MDA (i.e., MDMA); that is, a (+)amphetamine stimulus (MDMC: ED50 = 2.36 mg/kg) but not a DOM stimulus generalized to MDMC. In MDMA-trained rats, stimulus generalization occured both to MDC and MDMC (ED50 = 1.64 and 1.60 mg/kg, respectively). Although this and previous studies have demonstrated that significant parallelisms exist between the structure–activity relationships of amphetamine analogs and cathinone analogs, we now report several unexpected qualitative and/or quantitative differences. It is suggested that caution be used in attempting to draw conclusions or make predictions about the activity and potency of novel cathinone analogs by analogy to the structure–activity relationships derived from amphetamine-related agents; it would appear that each new cathinone analog will require individual investigation.
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Cocaine-stimulus generalization to two new designer drugs : Methcathinone and 4-methylaminorex
Pharmacology biochemistry and behavior, 1993Co-Authors: Richard Young, Richard A. GlennonAbstract:Rats were trained to discriminate 8 mg/kg cocaine from saline vehicle for the purpose of examining the stimulus properties of two novel and structurally related drugs of abuse recently confiscated on the illicit market: (+/-)Methcathinone and cis(+/-)4-methylaminorex. The stimulus properties of these controlled substance analogs were compared with those of their parent compounds (+/-)cathinone and aminorex, respectively. All agents resulted in cocaine-stimulus generalization with the following rank order of potency: aminorex (ED50 value = 0.8 microM/kg) > Methcathinone (1.9 microM/kg) > cathinone (3.7 microM/kg) > 4-methylaminorex (5.2 microM/kg) > cocaine (7.6 microM/kg).
Donald M Kuhn - One of the best experts on this subject based on the ideXlab platform.
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differential effects of synthetic psychoactive cathinones and amphetamine stimulants on the gut microbiome in mice
PLOS ONE, 2020Co-Authors: Mariana Angoaperez, Branislava Zagorac, Andrew D Winters, Jonathan M Greenberg, Madison M Ahmad, Kevin R Theis, Donald M KuhnAbstract:The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka "Bath Salts") and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), Methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a β-keto substituent (Methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time- and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (Methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (Methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.
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dissociation between hypothermia and neurotoxicity caused by mephedrone and Methcathinone in tph2 knockout mice
Psychopharmacology, 2019Co-Authors: John H Anneken, Mariana Angoaperez, Donald M Kuhn, Girish C Sati, David CrichAbstract:Mephedrone is a commonly abused constituent of “bath salts” and has many pharmacological effects in common with methamphetamine. Despite their structural similarity, mephedrone differs significantly from methamphetamine in its effects on core body temperature and dopamine nerve endings. The reasons for these differences remain unclear. Mephedrone elicits a transient hypothermia which may provide intrinsic neuroprotection against methamphetamine-like toxicity to dopamine nerve endings. Furthermore, evidence in the literature suggests that this hypothermia is mediated by serotonin. By utilizing transgenic mice devoid of brain serotonin, we determined the contribution of this neurotransmitter to changes in core body temperature as well as its possible role in protecting against neurotoxicity. The effects of Methcathinone and 4-methyl-methamphetamine, two structural analogs of mephedrone and methamphetamine, were also evaluated in these mice. The hypothermia induced by mephedrone and Methcathinone in wild-type mice was not observed in mice lacking brain serotonin. Despite preventing drug-induced hypothermia, the lack of serotonin did not alter the neurotoxic profiles of the test drugs. Serotonin is a key mediator of pharmacological hypothermia induced by mephedrone and Methcathinone, but these body temperature effects do not contribute to dopamine nerve ending damage observed in mice following treatment with mephedrone, Methcathinone or 4-methyl-methamphetamine. Thus, the key component of methamphetamine neurotoxicity lacking in mephedrone remains to be elucidated.
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dissociation between hypothermia and neurotoxicity caused by mephedrone and Methcathinone in tph2 knockout mice
Psychopharmacology, 2019Co-Authors: John H Anneken, Mariana Angoaperez, Girish C Sati, David Crich, Donald M KuhnAbstract:Rationale Mephedrone is a commonly abused constituent of “bath salts” and has many pharmacological effects in common with methamphetamine. Despite their structural similarity, mephedrone differs significantly from methamphetamine in its effects on core body temperature and dopamine nerve endings. The reasons for these differences remain unclear.
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mephedrone an abused psychoactive component of bath salts and methamphetamine congener does not cause neurotoxicity to dopamine nerve endings of the striatum
Journal of Neurochemistry, 2012Co-Authors: Mariana Angoaperez, Michael J Kane, Dina M Francescutti, Katherine E Sykes, Mrudang Shah, Abiy M Mohammed, David M Thomas, Donald M KuhnAbstract:Mephedrone (4-methylMethcathinone) is a β-ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the US and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and Methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge-like regimen of mephedrone (4X 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum.
George A Ricaurte - One of the best experts on this subject based on the ideXlab platform.
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reduced striatal dopamine transporter density in abstinent methamphetamine and Methcathinone users evidence from positron emission tomography studies with 11c win 35 428
The Journal of Neuroscience, 1998Co-Authors: Una D Mccann, Dean Foster Wong, Fuji Yokoi, Victor L Villemagne, Robert F Dannals, George A RicaurteAbstract:Methamphetamine and Methcathinone are psychostimulant drugs with high potential for abuse. In animals, methamphetamine and related drugs are known to damage brain dopamine (DA) neurons, and this damage has recently been shown to be detectable in living nonhuman primates by means of positron emission tomography (PET) with [ 11 C]WIN-35,428, a DA transporter (DAT) ligand. The present studies determined whether living humans with a history of methamphetamine or Methcathinone abuse showed evidence of lasting decrements in brain DAT density. PET studies were performed in 10 control subjects, six abstinent methamphetamine users, four abstinent Methcathinone users, and three patients with Parkinson’s disease (PD). On average, subjects had abstained from amphetamine use for ∼3 years. Before PET studies, all subjects underwent urine and blood toxicology screens to rule out recent drug use. Compared with controls, abstinent methamphetamine and Methcathinone users had significant decreases in DAT density in the caudate nucleus (−23 and −24%, respectively) and putamen (−25 and −16%, respectively). Larger decreases in DAT density were evident in patients with PD (47 and 68% in caudate and putamen, respectively). Neither methamphetamine nor Methcathinone users showed clinical signs of parkinsonism. Persistent reductions of DAT density in methamphetamine and Methcathinone users are suggestive of loss of DAT or loss of DA terminals and raise the possibility that as these individuals age, they may be at increased risk for the development of parkinsonism or neuropsychiatric conditions in which brain DA neurons have been implicated.
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Reduced striatal dopamine transporter density in abstinent methamphetamine and Methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428
1998Co-Authors: Una D Mccann, Dean Foster Wong, Fuji Yokoi, Victor L Villemagne, Robert F Dannals, George A RicaurteAbstract:Methamphetamine and Methcathinone are psychostimulant drugs with high potential for abuse. In animals, methamphetamine and related drugs are known to damage brain dopamine (DA) neurons, and this damage has recently been shown to be detectable in living nonhuman primates by means of positron emission tomography (PET) with [ 11 C]WIN-35,428, a DA transporter (DAT) ligand. The present studies determined whether living humans with a history of methamphetamine or Methcathinone abuse showed evidence of lasting decrements in brain DAT density. PET studies were performed in 10 control subjects, six abstinent methamphetamine users, four abstinent Methcathinone users, and three patients with Parkinson’s disease (PD). On average, subjects had abstained from amphetamine use for �3 years. Before PET studies, all subjects underwent urine and blood toxicology screens to rule out recen
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neurotoxic and pharmacologic studies on enantiomers of the n methylated analog of cathinone Methcathinone a new drug of abuse
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: M Sparago, J Wlos, Jie Yuan, George Hatzidimitriou, J Tolliver, T Dal A Cason, Jonathan L Katz, George A RicaurteAbstract:These studies evaluated neurotoxic and pharmacologic properties of the R(+) and S(-) enantiomers of Methcathinone, a psychostimulant drug that has surfaced in the illicit drug market, primarily in the S(-) form. Neurotoxic potential toward brain dopamine (DA) and serotonin (5-HT) neurons was assessed by measuring DA and 5-HT axonal markers and by means of silver degeneration studies; pharmacologic effects were evaluated by measuring locomotor stimulation. Methcathinone produced dose-related neurotoxic and locomotor stimulant effects which were species- and enantiomer-dependent. In mice, although both enantiomers produced toxic effects on DA neurons, the R(+) enantiomer was more potent, and neither enantiomer produced long-term effects on 5-HT neurons. By contrast, in behavioral studies, both enantiomers increased mouse locomotor activity, but the S(-) enantiomer was more potent, which suggests that Methcathinone's neurotoxic and locomotor stimulant effects may be separable. Additional studies were done with rats, because mice are often refractory to 5-HT neurotoxicity induced by amphetamines. In the rat, both enantiomers produced toxic effects on DA neurons, only S(-)-Methcathinone produced toxic effects on 5-HT neurons, and both enantiomers produced comparable locomotor stimulant effects. Together, these results indicate that: 1) Methcathinone has the potential to damage DA and 5-HT neurons; 2) Methcathinone neurotoxicity is enantiomer and species dependent; 3) Methcathinone's neurotoxic and locomotor stimulant effects are dissociable in mice but not rats; and 4) N-methylation confers 5-HT toxic activity onto cathinone, the N-desmethyl derivative of Methcathinone, which is known to lack 5-HT neurotoxic activity.
Richard Young - One of the best experts on this subject based on the ideXlab platform.
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in vitro characterization of ephedrine related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Richard B Rothman, Richard Young, John S Partilla, Bryan L Roth, Sandra J Hufeisen, Beth Ann Comptontoth, Jon Birkes, Richard A. GlennonAbstract:Ephedrine is a long-studied stimulant available both as a prescription and over-the-counter medication, as well as an ingredient in widely marketed herbal preparations, and is also used as a precursor for the illicit synthesis of methamphetamine. Ephedrine is related to phenylpropanolamine, a decongestant removed from the market place due to concerns that its use increased the risk of hemorrhagic stroke. Standard pharmacology texts emphasize that ephedrine is both a direct and indirect adrenergic agonist, activating adrenergic receptors both by direct agonist activity as well as by releasing norepinephrine via a carrier-mediated exchange mechanism. Chemically, ephedrine possesses two chiral centers. In the present study, we characterized the stereoisomers of ephedrine and the closely related compounds pseudoephedrine, norephedrine, pseudonorephedrine (cathine), Methcathinone, and cathinone at biogenic amine transporters and a large battery of cloned human receptors (e.g., “receptorome”). The most potent actions of ephedrine-type compounds were as substrates of the norepinephrine transporter (EC 50 values of about 50 nM) followed by substrate activity at the dopamine transporter. Screening the receptorome demonstrated weak affinity at α 2 -adrenergic and 5-hydroxytryptamine 7 receptors ( K i values 1–10 μM) and no significant activity at β-adrenergic or α 1 -adrenergic receptors. Viewed collectively, these data indicate that the pharmacological effects of ephedrine-like phenylpropanolamines are likely mediated by norepinephrine release, and although sharing mechanistic similarities with, they differ in important respects from those of the phenylpropanonamines Methcathinone and cathinone and the phenyisopropylamines methamphetamine and amphetamine.
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Cathinone: An Investigation of Several N -Alkyl and Methylenedioxy-Substituted Analogs
Pharmacology biochemistry and behavior, 1997Co-Authors: Terry A. Dal Cason, Richard Young, Richard A. GlennonAbstract:DAL CASON, T. A., R. YOUNG AND R. A. GLENNON. Cathinone: An investigation of several N-alkyl and methylenedioxy-substituted analogs. PHARMACOL BIOCHEM BEHAV 58(4) 1109–1116, 1997.—Structurally, Methcathinone is to cathinone what methamphetamine is to amphetamine. Due to increased interest in the abuse of such agents we wished to determine if certain derivatives of cathinone would behave in a manner consistent with what is known about their amphetamine counterparts; that is, can amphetamine structure–activity relationships be extrapolated to cathinone analogs? As expected on the basis of known structure–activity relationships for amphetaminergic agents, both N-monoethylcathinone and N-mono-n-propylcathinone (N-Et CAT and N-Pr CAT; ED50 = 0.77 and 2.03 mg/kg, respectively) produced amphetamine-like stimulus effects in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle and were somewhat less potent than racemic Methcathinone. In contrast, (−)N,N-dimethylcathinone or (−)Di Me CAT (ED50 = 0.44 mg/kg) was more potent than expected; although (+)N,N-dimethylamphetamine is sevenfold less potent than (+)methamphetamine, (−)Di Me CAT is only about 1.6-fold less potent than (−)Methcathinone, and is essentially equipotent with (−)cathinone. In addition, although it has been previously demonstrated that 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) results in stimulus generalization in rats trained to discriminate (+)amphetamine or DOM from vehicle, the cathinone counterpart of MDA (i.e., MDC) resulted in partial (maximum: 58%) generalization in (+)amphetamine-trained animals, and failed to produce >7% DOM-appropriate responding in rats trained to discriminate DOM from vehicle. On the other hand, the N-methyl analog of MDC (i.e., MDMC) behaved in a manner similar to that of the N-methyl analog of MDA (i.e., MDMA); that is, a (+)amphetamine stimulus (MDMC: ED50 = 2.36 mg/kg) but not a DOM stimulus generalized to MDMC. In MDMA-trained rats, stimulus generalization occured both to MDC and MDMC (ED50 = 1.64 and 1.60 mg/kg, respectively). Although this and previous studies have demonstrated that significant parallelisms exist between the structure–activity relationships of amphetamine analogs and cathinone analogs, we now report several unexpected qualitative and/or quantitative differences. It is suggested that caution be used in attempting to draw conclusions or make predictions about the activity and potency of novel cathinone analogs by analogy to the structure–activity relationships derived from amphetamine-related agents; it would appear that each new cathinone analog will require individual investigation.
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Cocaine-stimulus generalization to two new designer drugs : Methcathinone and 4-methylaminorex
Pharmacology biochemistry and behavior, 1993Co-Authors: Richard Young, Richard A. GlennonAbstract:Rats were trained to discriminate 8 mg/kg cocaine from saline vehicle for the purpose of examining the stimulus properties of two novel and structurally related drugs of abuse recently confiscated on the illicit market: (+/-)Methcathinone and cis(+/-)4-methylaminorex. The stimulus properties of these controlled substance analogs were compared with those of their parent compounds (+/-)cathinone and aminorex, respectively. All agents resulted in cocaine-stimulus generalization with the following rank order of potency: aminorex (ED50 value = 0.8 microM/kg) > Methcathinone (1.9 microM/kg) > cathinone (3.7 microM/kg) > 4-methylaminorex (5.2 microM/kg) > cocaine (7.6 microM/kg).
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Cocaine-stimulus generalization to two new designer drugs: Methcathinone and 4-methylaminorex. Pharmacol Biochem Behav
1993Co-Authors: Richard Young, Richard A. GlennonAbstract:YOUNG, R. AND R. A. GLENNON. Cocaine-stimulus generalization to two new designer drugs: Methcathinone and 4-methylaminorex. PHARMACOL BIOCHEM BEHAV 45(1) 229-231, 1993.-Rats were trained to discriminate 8 mg/kg cocaine from saline vehicle for the purpose of examining the stimulus properties of two novel and structurally related drugs of abuse recently confiscated on the illicit market: (+)Methcathinone and c/s(+ )4-methylaminorex. The stimulus properties of these controlled substance analogs were compared with those of their parent compounds (+)cathinone and aminorex, respectively. All agents resulted in cocaine-stimulus generalization with the following rank order of potency: aminorex (ED~0 value = 0.8 #M/kg) > Methcathinone (1.9 #M/kg) > cathinone (3.7 #M/kg) > 4-methylaminorex (5.2 #M/kg) > cocaine (7.6/LM/kg)
Mariana Angoaperez - One of the best experts on this subject based on the ideXlab platform.
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differential effects of synthetic psychoactive cathinones and amphetamine stimulants on the gut microbiome in mice
PLOS ONE, 2020Co-Authors: Mariana Angoaperez, Branislava Zagorac, Andrew D Winters, Jonathan M Greenberg, Madison M Ahmad, Kevin R Theis, Donald M KuhnAbstract:The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka "Bath Salts") and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), Methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a β-keto substituent (Methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time- and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (Methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (Methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.
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dissociation between hypothermia and neurotoxicity caused by mephedrone and Methcathinone in tph2 knockout mice
Psychopharmacology, 2019Co-Authors: John H Anneken, Mariana Angoaperez, Donald M Kuhn, Girish C Sati, David CrichAbstract:Mephedrone is a commonly abused constituent of “bath salts” and has many pharmacological effects in common with methamphetamine. Despite their structural similarity, mephedrone differs significantly from methamphetamine in its effects on core body temperature and dopamine nerve endings. The reasons for these differences remain unclear. Mephedrone elicits a transient hypothermia which may provide intrinsic neuroprotection against methamphetamine-like toxicity to dopamine nerve endings. Furthermore, evidence in the literature suggests that this hypothermia is mediated by serotonin. By utilizing transgenic mice devoid of brain serotonin, we determined the contribution of this neurotransmitter to changes in core body temperature as well as its possible role in protecting against neurotoxicity. The effects of Methcathinone and 4-methyl-methamphetamine, two structural analogs of mephedrone and methamphetamine, were also evaluated in these mice. The hypothermia induced by mephedrone and Methcathinone in wild-type mice was not observed in mice lacking brain serotonin. Despite preventing drug-induced hypothermia, the lack of serotonin did not alter the neurotoxic profiles of the test drugs. Serotonin is a key mediator of pharmacological hypothermia induced by mephedrone and Methcathinone, but these body temperature effects do not contribute to dopamine nerve ending damage observed in mice following treatment with mephedrone, Methcathinone or 4-methyl-methamphetamine. Thus, the key component of methamphetamine neurotoxicity lacking in mephedrone remains to be elucidated.
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dissociation between hypothermia and neurotoxicity caused by mephedrone and Methcathinone in tph2 knockout mice
Psychopharmacology, 2019Co-Authors: John H Anneken, Mariana Angoaperez, Girish C Sati, David Crich, Donald M KuhnAbstract:Rationale Mephedrone is a commonly abused constituent of “bath salts” and has many pharmacological effects in common with methamphetamine. Despite their structural similarity, mephedrone differs significantly from methamphetamine in its effects on core body temperature and dopamine nerve endings. The reasons for these differences remain unclear.
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mephedrone an abused psychoactive component of bath salts and methamphetamine congener does not cause neurotoxicity to dopamine nerve endings of the striatum
Journal of Neurochemistry, 2012Co-Authors: Mariana Angoaperez, Michael J Kane, Dina M Francescutti, Katherine E Sykes, Mrudang Shah, Abiy M Mohammed, David M Thomas, Donald M KuhnAbstract:Mephedrone (4-methylMethcathinone) is a β-ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the US and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and Methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge-like regimen of mephedrone (4X 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum.