Analytical Pharmacology and Drug Discovery of the Oxytocin Receptor: Towards Ameliorating Neuropsychiatric Disorders and the Global Burden of Disease

Abstract

Oxytocin (OT) is a neuropeptide that facilitates social behaviour, biological development, cognitive processing, and physiological homeostasis. Accordingly, the OT receptor (OTR) has shown remarkable therapeutic potential against some of the largest contributors to the global burden of disease, including neuropsychiatric disorders, cardiometabolic disease, pain, and inflammation. However, the cross-activity of OT at the vasopressin (AVP) 1a receptor (V1aR), particularly in some rodent studies, has diminished confidence in the OTR as a valid drug target. Additionally, while in prior work, the author and colleagues developed the first small molecule OTR agonists, unclear or suboptimal pharmacodynamics and pharmacokinetics hinders their progression as suitable drug candidates. This thesis utilises the principles of analytical pharmacology towards improving OTR drug discovery across these domains. Cell signalling assays and the operational model revealed less OT/AVP cross-activity at the OTR and V1aR for humans than mice, and at the V1aR than the OTR. This pattern suggests that targeting the OTR is appropriate for harnessing therapeutic effects of OT in humans. The same approach with small molecule agonists incorporating fluorescent biosensors and signalling kinetics elucidated functional affinity, intrinsic efficacy, G protein family bias, and structure-activity relationships. Derivatives with protected metabolic liabilities displayed enhanced selectivity against the V1aR and V2 receptor, with limited endosomal signalling at the latter, indicating greater off-target safety. Rigorous assessment of novel scaffolds uncovered the first synthetic OTR positive allosteric modulators, which may potentiate endogenous signalling patterns, and defined their cooperativity, affinity, probe dependence, receptor selectivity, and species translatability. Beyond these primary achievements, this thesis introduces advanced pharmacological techniques for all receptors.