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

doi:10.1016/j.ejmech.2017.10.059

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

Eur J Med Chem. 2018 Jan 1:143:1644-1656. doi: 10.1016/j.ejmech.2017.10.059. Epub 2017 Oct 23.

Authors

William T Jorgensen¹, Damien W Gulliver², Timothy A Katte¹, Eryn L Werry², Tristan A Reekie¹, Mark Connor³, Michael Kassiou⁴

Affiliations

¹ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
² Faculty of Health Sciences and School of Medical Sciences (Pharmacology), Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.
³ Faculty of Medicine and Health Sciences, Macquarie University, NSW 2109, Australia.
⁴ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.

PMID: 29126725
DOI: 10.1016/j.ejmech.2017.10.059

Abstract

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 (V_1aR). 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 V_1aR pharmacology when compared to 1. A general trend was observed in V_1aR 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 V_1aR.

Keywords: Arginine vasopressin 1(a) receptor; Diazepine; Oxytocin receptor; WAY-267,464.

MeSH terms

Benzodiazepines / chemical synthesis
Benzodiazepines / chemistry
Benzodiazepines / pharmacology*
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Molecular Conformation
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Receptors, Oxytocin / antagonists & inhibitors*
Receptors, Vasopressin / metabolism*
Structure-Activity Relationship

Substances

4-(3,5-dihydroxybenzyl)-N-(2-methyl-4-((1-methyl-4,10-dihydropyrazolo(3,4-b)(1,5)benzodiazepin-5(1H)-yl)carbonyl)benzyl)piperazine-1-carboxamide
AVPR1A protein, human
OXTR protein, human
Pyrazoles
Receptors, Oxytocin
Receptors, Vasopressin
Benzodiazepines