Pharmacological Characterisation of Novel Oxytocin and Vasopressin Receptor Ligands

Abstract

Deficits in social behavioural domains such as interpersonal communication and emotion recognition are a symptom of many neuropsychiatric conditions, including autism spectrum disorder, schizophrenia and social anxiety disorder. Often, these symptoms are intractable, profoundly affecting patient quality of life. Current therapeutic interventions do not target core social deficits and display considerable adverse effect profiles, thus, novel approaches are urgently needed to address the medical needs of this patient population. The hypothalamic peptides oxytocin (OT) and vasopressin (AVP) have emerged as key regulators of social behaviour in vertebrates, with converging evidence indicating that OT signalling exerts broadly prosocial effects in animal studies and human cohorts. Consequently, the oxytocin receptor (OTR) has been identified as a potential therapeutic target for improving social behavioural deficits. The use of OT in this context is complicated by rapid metabolism and poor CNS penetration of the peptide, low receptor selectivity between the OTR and vasopressin receptors (V1aR, V1bR, V2R) and desensitisation of the OTR with chronic administration. This thesis sought to identify OTR agonists which mitigate limitations inherent to the native peptide. Drug candidates were screened from a library of (A) pyrazolobenzodiazepine small molecules and (B) peptide ligands derived from endogenous metabolites of OT. Although the small-molecule discovery program did not identify novel OTR agonists, two selective V1aR ligands (4a, 5f) were characterised, which may have alternate therapeutic applications. In contrast, the peptide discovery program identified biologically active fragments of OT (9a, 9b). Structural modification of these metabolites produced selective OTR agonists (11c, 12c) with enhanced receptor affinity and signalling efficacy. Relative to OT, these modified peptides displayed a bias toward activation of G-protein signalling, and away from b-arrestin recruitment – factors which may prolong therapeutic efficacy in vivo. The lower molecular weight and reduced polarity of 11c and 12c relative to OT may also facilitate greater CNS penetration, positioning them as superior candidates for further development as oxytocinergic therapeutics.