Background and PurposeThere 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‐ (orpara‐)substituted analogues ofMCAT. Specifically, the steric character (Taft's stericES) of the 4‐position substituent affectedin vitropotency to induce monoamine release via dopamine and 5‐HT transporters (DATandSERT) andin vivomodulation of intracranial self‐stimulation (ICSS). Here, we have assessed the effects of other steric properties of the 4‐position substituents.Experimental ApproachDefinitive steric parameters that more explicitly focus on the volume, width and length of theMCAT4‐position substituents were assessed. In addition, homology models of humanDATand humanSERTbased upon the crystallizedDrosophila DATwere constructed and docking studies were performed, followed by hydropathic interaction (HINT) analysis of the docking results.Key ResultsThe potency of sevenMCATanalogues atDATwas negatively correlated with the volume and maximal width of their 4‐position substituents, whereas potency atSERTincreased as substituent volume and length increased.SERT/DATselectivity, as well as abuse‐related drug effects in theICSSprocedure, also correlated with the same parameters. Docking solutions offered a means of visualizing these findings.Conclusions and ImplicationsThese results suggest that steric aspects of the 4‐position substituents ofMCATanalogues are key determinants of their action and selectivity, and that the hydrophobic nature of these substituents is involved in their potency atSERT.