Flexible analogues of WAY-267,464: Synthesis and pharmacology at the human oxytocin and vasopressin 1a receptors

William T Jorgensen; Damien W Gulliver; Eryn L Werry; Tristan Reekie; Mark Connor; Michael Kassiou

doi:10.1016/j.ejmech.2015.11.050

Flexible analogues of WAY-267,464: Synthesis and pharmacology at the human oxytocin and vasopressin 1a receptors

Eur J Med Chem. 2016 Jan 27:108:730-740. doi: 10.1016/j.ejmech.2015.11.050. Epub 2015 Dec 13.

Authors

William T Jorgensen¹, Damien W Gulliver², Eryn L Werry³, Tristan Reekie¹, Mark Connor⁴, Michael Kassiou⁵

Affiliations

¹ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
² School of Medical Sciences (Pharmacology), Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.
³ Faculty of Health Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
⁴ Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, NSW 2109, Australia.
⁵ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia; Faculty of Health Sciences, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.

PMID: 26741855
DOI: 10.1016/j.ejmech.2015.11.050

Abstract

A previously identified, non-peptidic oxytocin (OT) receptor agonist WAY-267,464 (1) and nine novel derivatives (3, 4a-7a, 4b-7b) were synthesised and evaluated in vitro with the aim of systematically exploring hydrogen bonding interactions and ligand flexibility. All analogues were subjected to competition radioligand binding assays at human oxytocin (OT) and arginine vasopressin 1a (V1a) receptors. Physiological activity was determined using whole cell IP1 accumulation assays. Under these conditions, WAY-267,464 had higher affinity for the V1a receptor compared to the OT receptor (8.5x more selective) with poor functional selectivity (2x selective for OT receptor agonism over V1a receptor antagonism). Methylation of the resorcinol moiety (3) reversed the OT receptor pharmacological profile, removing agonist activity and inducing antagonist activity, without altering V1a receptor pharmacology. All flexible tethered derivatives removed OT receptor affinity and activity resulting in the generation of highly selective V1a receptor ligands.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzodiazepines / chemical synthesis
Benzodiazepines / chemistry
Benzodiazepines / pharmacology*
Dose-Response Relationship, Drug
Humans
Ligands
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Receptors, Oxytocin / agonists*
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
Ligands
Pyrazoles
Receptors, Oxytocin
Receptors, Vasopressin
Benzodiazepines