Structure Activity Relationship Study of Cannabinoid Receptor 1 Ligands

Abstract

This thesis describes the design, synthesis and pharmacological evaluation of a library of CB1 orthosteric and allosteric ligands. Synthetic cannabinoids (SCs) have emerged in the public domain as a ‘legal’ alternative to cannabis. These drugs are based on experimental cannabinoid 1 receptor (CB1) agonists that were investigated as potential treatments for neuropathic pain. As these compounds have not gone through any formal human testing, they have been associated with an array unpredictable, and often serious, adverse effects. The initial focus of this work was to synthesise recent high concern SCs and their major phase 1 metabolites, and access their cannabimimetic activity in vitro and in vivo. An efficient, divergent synthesis was utilised to access a library of SCs. Using a FLIPR assay with AtT20 cells transfected with either hCB1 or hCB2, the series of SCs synthesised proved to be some of the most potent and efficacious cannabinoid ligands recorded to date. Their cannabimimetic activity was verified in vivo, where select SCs caused a characteristic hypothermic and bradycardic response in a rat model. In contrast to the phytocannabinoids, the major metabolites of SCs retain activity at both cannabinoid receptors, and also have activity at key off-site receptors TRPA1 and TRPV1, potentially contributing to the overall pharmacological profiles of the drugs. With limited potential as therapeutics, classes of compounds beyond CB1 agonists are being investigated to modulate the endocannabinoid system. ZCZ-011 has shown promising in vivo and in vitro results as a positive allosteric modulator (PAM) at CB1. As there was insufficient structure activity analysis conducted on this compound, modifications were made to the lead structure to investigate the key binding requirements of CB1 allosteric binding, incorporating key features of other CB1 PAMs. These compounds are currently undergoing in vitro evaluation.