The Oxytocin Agonist WAY267464 Is Also A Potent Vasopressin 1A Antagonist

Background: Intranasal and intravenous (i.v.) administration of oxytocin improves autism symptoms in adults and adolescent autistic subjects. Due to the short half-life of the oxytocin peptide in blood and cerebrospinal fluid, it would be highly useful to identify a brain penetrant small molecule oxytocin receptor agonist for the treatment of autism. Such a potential compound, WAY267464, was described by Ring et al (2009) as a specific oxytocin receptor agonist, with more than 100 fold selectivity against the related V1a, V1b and V2 vasopressin receptors. In vivo the compound reversed stimulant-induced pre-pulse inhibition and had anxiolytic activity after intraperitoneal administration.

Objectives: To profile the in vitro activity of the compound and confirm its affinity for the oxytocin receptor and selectivity against related receptors. We also investigated the pharmacokinetic profile of WAY267464 in rats after i.v. and oral administration.

Methods: WAY267464 was synthetized in-house and profiled in radioligand binding as well as calcium flux functional assays (FLIPR) using recombinant cell lines stably expressing the human or rodent oxytocin or vasopressin receptors.

Results: Using FLIPR, we confirm that WAY267464 is a human oxytocin receptor agonist with EC50= 44 nM +/- 20 and 77% efficacy compared to the maximum effect of oxytocin (EC50= 3nM, 100% efficacy). This is in line with the values reported by Ring et al (2009) on the human oxytocin receptor (EC50= 61nM, 87% efficacy). Surprisingly we find that WAY267464 is also a potent antagonist on the human V1a (binding Ki= 73nM, functional Kb= 78 nM) as well as mouse V1a receptor (binding Ki= 278 nM, functional Kb= 97 nM).
In vivo pharmacokinetic analysis showed that the compound has fast clearance after intravenous administration and poor brain penetration.

Conclusions: In order to dissect the contribution of the oxytocinergic or vasopressinergic system to autism and social behavior in general, it is important to have selective tool compounds available. WAY267464 is described as a selective oxytocin agonist, but we found that it is also a potent human and mouse vasopressin V1a receptor antagonist. This may affect the interpretation of behavioral results obtained with WAY267464.