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.