Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure–Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs
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.
KeywordsDopamine transporter Flephedrone Intracranial self-stimulation Mephedrone Methcathinone Methedrone Microdialysis Serotonin transporter Structure–activity relationship
This work was supported by R01 DA033930.
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