Structural Insights into 5-HT1A/D4 Selectivity of WAY-100635 Analogues: Molecular Modeling, Synthesis, and in Vitro Binding

The resurgence of interest in 5-HT1A receptors as a therapeutic target requires the existence of highly selective 5-HT1A ligands. To date, WAY-100635 has been the prototypical antagonist of these receptors. However, this compound also has significant affinity for and activity at D-4 dopamine receptors. In this context, this work was aimed at better understanding the 5-HT1A/D-4 selectivity of WAY-100635 and analogues from a structural point of view. In silico investigations revealed two key interactions for the 5-HT1A/D-4 selectivity of WAY-100635 and analogues. First, a hydrogen bond only found with the Ser 7.36 of D-4 receptor appeared to be the key for a higher D4 affinity for newly synthesized aza analogues. The role of Ser 7.36 was confirmed as the affinity of aza analogues for the mutant D-4 receptor S7.36A was reduced. Then, the formation of another hydrogen bond with the conserved Ser 5.42 residue appeared to be also critical for D-4 binding.