Chapter

Neuropharmacology of New Psychoactive Substances (NPS)

Volume 32 of the series Current Topics in Behavioral Neurosciences pp 119-131

Date:

Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure–Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs

  • S. Stevens NegusAffiliated withDepartment of Pharmacology and Toxicology, Virginia Commonwealth University Email author 
  • , Matthew L. BanksAffiliated withDepartment of Pharmacology and Toxicology, Virginia Commonwealth University

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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.

Keywords

Dopamine transporter Flephedrone Intracranial self-stimulation Mephedrone Methcathinone Methedrone Microdialysis Serotonin transporter Structure–activity relationship