Conformationally rigid derivatives of WAY-267,464: Synthesis and pharmacology at the human oxytocin and vasopressin-1a receptors

WAY-267,464 (1) and twelve conformationally rigid analogues (3a-f–4a-f) were synthesised, characterised and evaluated in cellular assays with the aim of systematically exploring interactions with the oxytocin receptor (OTR). Each analogue was evaluated in radioligand binding displacement assays at both human OTR and arginine vasopressin 1a receptors (V1aR). Physiological characterisation was determined by whole cell IP1 accumulation assays on stably transfected human embryonic kidney (HEK) cells. Incorporation of the rigid, optionally substituted benzene ring abolished OTR activity and diminished V1aR pharmacology when compared to 1. A general trend was observed in V1aR affinity for the propyl analogues (3d-3f) which identified the ortho-substituted analogue as the best in series (Ki = 251 nM) followed by a decrease in affinity through the meta and para-derivatives (3e; Ki = 874 nM and 3f; Ki = 1756 nM respectively). This study confirms the importance of the central pharmacophoric motifs of WAY-267,464 and illuminates the differences in the binding pocket of the highly conserved OTR and V1aR. [Display omitted] •Synthesis of 12 analogues of WAY-267,464.•Investigated the ideal linker conformation for OTR and V1aR pharmacophore.•Modifications abolished OTR pharmacology and reduced V1aR affinity in comparison to lead.•All analogues are investigated in competitive binding assays and functionally evaluated.