title: Flexible analogues of WAY-267,464: Synthesis and pharmacology at the human oxytocin and vasopressin 1a receptors.
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.
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: William T
authors.initials: WT
authors.lastname: Jorgensen
authors.affiliation: School of Medical Sciences (Pharmacology), Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Damien W
authors.initials: DW
authors.lastname: Gulliver
authors.affiliation: Faculty of Health Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Eryn L
authors.initials: EL
authors.lastname: Werry
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Tristan
authors.initials: T
authors.lastname: Reekie
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, NSW 2109, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Connor
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018045:Receptors, Oxytocin / Q000819:agonists*; D017483:Receptors, Vasopressin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C547280:4-(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; D008024:Ligands; D011720:Pyrazoles; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D001569:Benzodiazepines
keywords: Arginine vasopressin 1(a) receptor; Diazepine; Oxytocin receptor; WAY-267,464