A HYDROGEN BOND INFLUENCES THE 5-HT1A/D4 SELECTIVITY OF WAY-100635 ANALOGUES: AN IN SILICO APPROACH

WAY-100635 is widely used in vitro and in vivo as an antagonist of 5-HT1A receptors. In terms of pharmacological tools and pharmacological investigations, the ideal reference molecule would be highly selective for its target over other related and non-related targets. However WAY-100635 displays affinity for and activity at D4 dopamine receptors, and that "off-target" activity confounds its use in pharmacological studies, particularly when both receptors are present. In this context, we carried out various chemical modifications of the WAY-100635 structure in order to improve its 5-HT1A versus D4 selectivity. An important increase of
selectivity was obtained when the basic side chain of WAY-100635 was replaced by a 4-phenylpiperazine or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety. In contrast, the introduction of nitrogen atoms in the acyl group decreased the selectivity by reducing the affinity for 5-HT1A receptors, on the one hand, and enhancing the affinity for D4 receptors on the other hand. In order to explain the reduced 5-HT1A/D4 selectivity of aza-derivatives, the binding modes of the compounds were explored by docking analysis on homology models of the two receptors. It appears that the formation of an additional hydrogen bond within D4 receptors could be the key of the decreased selectivity. These results will be very helpful for developing molecules with an improved 5-HT1A/D4 selectivity.