Steric parameters, molecular modeling and hydropathic interaction analysis of the pharmacology of para-substituted methcathinone analogues.

Background and Purpose There is growing concern over the abuse of certain psychostimulant methcathinone ( MCAT) analogues. This study extends an initial quantitative structure-activity relationship ( QSAR) investigation that demonstrated important steric considerations of seven 4- (or para-)substituted analogues of MCAT. Specifically, the steric character ( Taft's steric E_S) of the 4-position substituent affected in vitro potency to induce monoamine release via dopamine and 5-HT transporters ( DAT and SERT) and in vivo modulation of intracranial self-stimulation ( ICSS). Here, we have assessed the effects of other steric properties of the 4-position substituents. Experimental Approach Definitive steric parameters that more explicitly focus on the volume, width and length of the MCAT 4-position substituents were assessed. In addition, homology models of human DAT and human SERT based upon the crystallized D rosophila DAT were constructed and docking studies were performed, followed by hydropathic interaction ( HINT) analysis of the docking results. Key Results The potency of seven MCAT analogues at DAT was negatively correlated with the volume and maximal width of their 4-position substituents, whereas potency at SERT increased as substituent volume and length increased. SERT/ DAT selectivity, as well as abuse-related drug effects in the ICSS procedure, also correlated with the same parameters. Docking solutions offered a means of visualizing these findings. Conclusions and Implications These results suggest that steric aspects of the 4-position substituents of MCAT analogues are key determinants of their action and selectivity, and that the hydrophobic nature of these substituents is involved in their potency at SERT. [ABSTRACT FROM AUTHOR]