mephedrone and clephedrone

Synthetic cathinones are a class of new psychoactive substances that display psychomotor stimulant properties, and novel cathinone analogs continue to emerge in illicit drug markets worldwide. The aim of the present study was to characterize the pharmacology of 4-chloro ring-substituted cathinones that are appearing in illicit drug markets compared with the effects of 4-methylmethcathinone (mephedrone). Synaptosomes were prepared from rat caudate for dopamine transporter (DAT) assays or from whole brain minus caudate and cerebellum for norepinephrine transporter (NET) and serotonin transporter (SERT) assays. Findings from transporter uptake inhibition and release assays showed that mephedrone and 4-chloromethcathinone (4-CMC) function as substrates at DAT, NET, and SERT, with similar potency at all three transporters. In contrast, 4-chloro-

Topics: Animals; Central Nervous System Agents; Central Nervous System Stimulants; Dopamine Plasma Membrane Transport Proteins; Humans; Illicit Drugs; Methamphetamine; Norepinephrine Plasma Membrane Transport Proteins; Rats; Serotonin Plasma Membrane Transport Proteins; Synthetic Cathinone

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.

Topics: Amphetamine; Animals; Behavior, Animal; Dopamine Plasma Membrane Transport Proteins; Fenfluramine; Humans; Methamphetamine; Methylamines; N-Methyl-3,4-methylenedioxyamphetamine; Norepinephrine Plasma Membrane Transport Proteins; Propiophenones; Psychotropic Drugs; Quantitative Structure-Activity Relationship; Rats; Self Administration; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship; Substance-Related Disorders