Oral Presentation Royal Australian Chemical Institute National Congress 2026

Novel oxytocin receptor agonists for the treatment of neuropsychiatric disorders (138173)

Timothy B Callis 1 2 , Eryn L Werry 3 , Michael Kassiou 4 , Tristan A Reekie 1 2
  1. School of Science, The University of New South Wales Canberra, Campbell, ACT, Australia
  2. Kinoxis Therapeutics, Melbourne, VIC, Australia
  3. Faculty of Health Sciences, The University of Sydney, Sydney, NSW, Australia
  4. School of Chemistry, The University of Sydney, Sydney, NSW, Australia

Activation of the oxytocin receptor (OTR) by its native neuropeptide ligand, oxytocin, is implicated in an array of central and peripheral nervous system processes, ranging from promoting prosocial behaviours to milk production for infant feeding, among others.1, 2 Its well-established role in promoting prosocial behaviour has identified it as a promising target for the treatment of several neuropsychiatric conditions such as depression and post-traumatic stress disorder.1  Despite success in the use of oxytocin to target the OTR in the periphery, its use for the treatment of central nervous system associated disorders has been severely hampered by poor blood-brain permeability, rapid metabolism, and off-target activity.  Although clinical attempts to utilise native oxytocin through formulation and administration optimisation have continued, no clinical success has been realised.3, 4 This highlights the need to develop new strategies to utilise the therapeutic potential of the OTR. Several structures have been reported as small molecule OTR agonists, however they are still limited by poor drug-like properties.1, 5-7 This work will report our work exploring novel small-molecule OTR targeting compounds that have been able to address the downfalls of native oxytocin and other reported OTR agonists. Extensive medicinal chemistry campaigns have identified structural motifs that promote OTR activity, reduce off-target activity, and improve pharmacokinetic profile. The success of this class of compounds has been illustrated across several in vitro and in vivo studies that illustrate the favourable activity profile and prosocial effect of this series.

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