Conformationally rigid derivatives of WAY-267,464

synthesis and pharmacology at the human oxytocin and vasopressin-1a receptors

William T. Jorgensen, Damien W. Gulliver, Timothy A. Katte, Eryn L. Werry, Tristan A. Reekie, Mark Connor, Michael Kassiou*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)


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.

Original languageEnglish
Pages (from-to)1644-1656
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 1 Jan 2018


  • arginine vasopressin 1a receptor
  • diazepine
  • oxytocin receptor
  • WAY-267,464

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