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Pharmacological Characterisation of Novel Oxytocin and Vasopressin Receptor Ligands

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Pharmacological Characterisation of Novel Oxytocin and Vasopressin Receptor Ligands Pharmacological Characterisation of Novel Oxytocin and Vasopressin Receptor Ligands Damien Gulliver A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Faculty of Medicine School of Medical Sciences The University of Sydney December 10th 2020 Statement of Originality I certify that to the best of my knowledge, this thesis contains no material previously published by any other person except where due acknowledgement has been made. This thesis has not been submitted for any degree or other purposes. I certify that the intellectual content of this thesis is the product of my own work and that all the assistance received in preparing this thesis and sources have been acknowledged. Damien Gulliver 30.09.20 Acknowledgements First and foremost, I would like to thank my supervisor, Prof. Michael Kassiou, for giving me the opportunity to work within the Drug Discovery Group on this project. A well-funded, smoothly running laboratory and interesting areas of research makes the experience of a PhD immeasurably more enjoyable. I appreciate the autonomy I was given to explore new ideas and establish new assays, and the direction I was given when it was sought after. Most of all, I appreciate your humour and your sensitivity, which shone through at the moments when I needed it most. To my colleague and mentor Dr. Eryn Werry - thank you for teaching me what it means to be a scientist. You have been there from the very beginning, since I was a fledgling honours student, and I can only say that without your steadfast support and gentle guidance, I would never have made it this far. Your unshakeable composure, easy-going nature and incredible abilities as a researcher leave me in awe, and I will always have boundless respect for you. To the chemists of the Drug Discovery Group { Dr. Will Jorgensen, Dr. Tristan Reekie and Timothy Katte. Thank you for your tireless efforts in synthesising the molecules investigated in this thesis. It was a pleasure to collaborate with you, and I appreciate the knowledge and technical expertise which you brought to various aspects of the oxytocin project. To my fellow students in the Drug Discovery Group { thank you for sharing this experience with me and I wish you all the best in future endeavours. Erick, I always felt that there was a tacit understanding between us, and I appreciated that solidarity. Kiyan, I admire your passion for science, I appreciate the assistance you provided me with the bias work, and I enjoyed our conversations around the intricacies of pharmacology. Michael, Alison and Sam { your presence created a positive and uplifting work environment which I valued immensely. I would also like to thank Donna Lai, Sheng Hua and the Molecular Biology Facility, who provided many of the instruments I used in this research, and the training on how to operate them. Thank you also to thank Dr. Ben Crossett and David Maltby from the Sydney Mass Spectrometry Core Facility, who tried valiantly for many months to assist me in establishing a mass-spectrometry assay, and to Dr. Markus Muttenthaler from the University of Queensland, who synthesised and generously gifted some of the molecules investigated in this thesis. To my friends and family, thank you for supporting me when I was low and sharing in my excitement when things were going well. A PhD can be a hard and sometimes dark road, but a strong network of people that love you provides much needed security, comfort and resilience. Athena, we met what feels like an age ago, and who knew then that we would go, as one, through the entire journey? We weathered the storms and celebrated the triumphs which arose through ten long years of study, and were shaped by them together. Many times, there was no one who truly understood how I felt but you. Thank you for your endlessly giving and caring nature, without which I would not be where I am, or who I am. Authorship Attribution Statement Chapter 1 of this thesis contains material published in: Gulliver D, Werry E, Reekie T, Katte T, Jorgensen W, Kassiou M.* Targeting the Oxytocin System: New Pharmacotherapeutic Approaches. Trends Pharmacol Sci. 2019;40(1):22-37. This has been adapted from the published manuscript, and is throughout Section 1.1 - 1.5. I conducted the literature review, wrote the manuscript and designed the figures for this publication. Chapter 3 of this thesis contains material published in: Jorgensen Wa, Gulliver Db, Katte T, Werry E, Reekie T, Connor M, Kassiou M.* Conformationally rigid derivatives of WAY-267,464: Synthesis and pharmacology at the human oxytocin and vasopressin 1A receptors. Eur J Med Chem. 2018;143:1644- 1656. This is Section 3.2.1; Figure 3.3 and Table 3.1, which corresponds to data in Table 1 of the published manuscript. I was involved in the experimental design, data collection, data management and statistical analysis for this publication. Chapter 5 of this thesis contains unpublished experimental data collected by Dr. Eryn Werry and included with her permission. This is in Section 5.3.3; Figure 5.4. In addition to the statements above, in cases where I am not the corresponding author of a published item, permission to include the published material has been granted by the corresponding author. Damien Gulliver 30.09.20 As supervisor for the candidature upon which this thesis is based, I can confirm that the authorship attribution statements above are correct. Michael Kassiou 30.09.20 Abstract Deficits in social behavioural domains such as interpersonal communication and emotion recognition are a symptom of many neuropsychiatric conditions, includ- ing 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 indicat- ing that OT signalling exerts broadly prosocial effects in animal studies and human cohorts. Consequently, the oxytocin receptor (OTR) has been identified as a poten- tial 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) pyra- zolobenzodiazepine small molecules and (B) peptide ligands derived from endoge- nous 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 discov- ery 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. List of Abbreviations 5-HT1A 5-HT type 1A receptor HEK293 Human epithelial kidney cells 5-HT1B 5-HT type 1B receptor HPA Hypothalamic-pituitary-adrenal ACTH Adrenocorticotropic hormone axis ADME Absorption, distribution, HTRF Homogenous time-resolved metabolism, excretion fluorescence ANOVA Analysis of variance IBMX 3-isobutyl-1-methyxanthine ASD Autism spectrum disorder ICV Intracerebroventricular AVP Arginine-vasopressin IMHB Intramolecular hydrogen bond AVPR Vasopressin receptor IP Intraperitoneal BRET Bioluminescence resonance IP1 Inositol monophosphate energy transfer IRAP Insulin-regulated aminopeptidase BSA Bovine serum albumin LB Luria-bertani broth cAMP Cyclic adenosine LC-MS Liquid chromatography-mass monophosphate spectrometry CB1 Cannabinoid type 1 receptor LVA Linear vasopressin CD38 Cyclic ADP ribose hydrolase MAPK Mitogen-activated protein CNS Central nervous system kinase CRH Corticotrophin-releasing hormone MCS Multiple cloning site CSF Cerebrospinal fluid MIF-1 Melanocyte inhibiting factor D2R Dopamine type 2 receptor NAcc Nucleus accumbens DMEM Dulbecco's modified eagle Nluc Nanoluciferase medium OT Oxytocin DMSO Dimethyl sulfoxide OTR Oxytocin receptor DRN Dorsal raphe nuclei OVTA Ornithine vasotocin ECL Extracellular loop PDE Phosphodiesterase EPSA Exposed polar surface area PET Positron emission tomography FBS Foetal bovine serum PKA Protein kinase A fMRI Functional magnetic resonance P-LAP Placental leucine imaging aminopeptidase FRET Fluorescence resonance energy PLGA Poly(lactic-co-glycolic acid) transfer PTSD Post-traumatic stress disorder GPCR G-protein coupled receptor PVN Paraventricular nuclei GRK G-protein coupled receptor kinase RAGE Receptor for advanced glycation HBSS Hank's buffered salts solution end products RCT Randomised controlled trial cation channel subfamily V member
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