Quantitative structure–activity relationship analysis of the pharmacology of para ‐substituted methcathinone analogues

Background and Purpose Methcathinone ( MCAT ) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4‐ CH 3 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 ( E s ), electronic ( σ p ) and lipophilic ( π p ) 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 S prague‐ D awley 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 E s 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 E s ) are key determinants of this selectivity.