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

Abstract

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 ES ) 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 Drosophila 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.

Figure 1

Relationship between (A) in vitro selectivity for DAT-versus-SERT-mediated monoamine release and the volume of the 4-position substituent (R = −0.972; P = 0.0002). (B) In vitro selectivity for DAT-versus-SERT-mediated monoamine release and maximal width (B5) (R = −0.917; P = 0.0039) and (C) between the volume of the 4-position substituent and maximal width (B5) (R = 0.935; P = 0.0020).

Figure 2

Superimposed poses of all seven MCAT analogues in the putative binding site of hDAT (A) and hSERT (B). Interacting amino acids within 5 Å are indicated. Unfavourable interactions of hDAT S149 with the 4-position substituents (shown for the 4-methoxy analogue; C) that are not seen in hSERT due to the smaller side chain of A169 (again, shown for the 4-methoxy analogue; D). The Connolly surface (shown in grey in C and D) represents the channels in both transporters.

Figure 3

Relationship between SERT in vitro potency (log EC₅₀) and (A) total HINT score, (B) polar HINT score and (C) hydrophobic HINT score.