The Design and Synthesis of Small Non-Peptide Oxytocin Receptor Ligands

Abstract

This thesis describes the design, synthesis and pharmacological evaluation of non-peptide based oxytocin receptor ligands for the treatment of mental disorders. The current work describes the investigation of pharmacophores for the oxytocin receptor based on scaffolds such as diazepines and elaborate carbazole derivatives as head groups. These cores were modified by altering heteroatoms, ring size and shape and adding a pendant cyclic amide. The pendant cyclic amide has been found to be a requisite for observing oxytocin receptor activation and changes to the core were made to synthesise a library of compounds. A tricyclic scaffold of a dibenzodiazepine headgroup with pendant cyclic amides showed modest activity for the oxytocin receptor. A dibenzodiazocine scaffold was found not to elicit an agonist effect on the oxytocin receptor but was found to have positive allosteric activity. This is the first ever reported discovery of an allosteric ligand for the oxytocin receptor. Further, a carbazole derivative with pendant cyclic amides were found to elicit an improved positive allosteric effect on the oxytocin receptor. This work also contains the exploration into the metabolism of oxytocin, the endogenous ligand for the oxytocin receptor. These metabolites were found to contain a key fragment of a 5-aminoacid sequence. From this key fragment, a more drug-like scaffold (mimetic) was designed to be synthesised which contained a trisubstituted phenyl ring with a pendant alcohol, tetrazole and indole. The synthesis of the mimetic was successful, and although no activity was found at the oxytocin receptor, an intermediate from this synthesis showed potent activity against methicillin-resistant staphylococcus aureus. A library of compounds was synthesised based on a N-benzylindole scaffold. Modifications to the indole were made and subsequently tested for activity against methicillin-resistant staphylococcus aureus in comparison to the lead.