title: Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure-Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs.
abstract: Many cathinone analogs act as substrates or inhibitors at dopamine, norepinephrine, and serotonin transporters (DAT, NET, SERT, respectively). Drug selectivity at DAT vs. SERT is a key determinant of abuse potential for monoamine transporter substrates and inhibitors, such that potency at DAT > SERT is associated with high abuse potential, whereas potency at DAT < SERT is associated with low abuse potential. Quantitative structure-activity relationship (QSAR) studies with a series of 4-substituted methcathinone analogs identified volume of the 4-position substituent on the methcathinone phenyl ring as one structural determinant of both DAT vs. SERT selectivity and abuse-related behavioral effects in an intracranial self-stimulation procedure in rats. Subsequent modeling studies implicated specific amino acids in DAT and SERT that might interact with 4-substituent volume to determine effects produced by this series of cathinone analogs. These studies illustrate use of QSAR analysis to investigate pharmacology of cathinones and function of monoamine transporters.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA. sidney.negus@vcuhealth.org.
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects*; D005277:Fenfluramine / Q000494:pharmacology; D006801:Humans; D008694:Methamphetamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012646:Self Administration; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects*; D013329:Structure-Activity Relationship; D019966:Substance-Related Disorders
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008744:Methylamines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011427:Propiophenones; D011619:Psychotropic Drugs; D050486:Serotonin Plasma Membrane Transport Proteins; D005277:Fenfluramine; C047806:monomethylpropion; D008694:Methamphetamine; C548233:mephedrone; C578181:4-fluoromethcathinone; D000661:Amphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C558328:4-methoxymethcathinone; C000602662:clephedrone
keywords: Dopamine transporter; Flephedrone; Intracranial self-stimulation; Mephedrone; Methcathinone; Methedrone; Microdialysis; Serotonin transporter; Structure–activity relationship