Cannabinoid Receptor Type 1 (CB1) : Design, Synthesis, and Basic Pharmacology of Novel Ligands

Abstract

Cannabinoid Receptor Type 1 (CB1) is the most abundant G-protein coupled receptor (GPCR) in the human brain and is of critical importance to the modulation of neuronal signal transmission and a multitude of downstream physiological processes. However, despite GPCRs representing the largest and arguably most important family of drug targets, clinical therapies which effectively target CB1 without eliciting adverse side effects remain elusive.1,2 Now withdrawn drug rimonabant lends its molecular scaffold to a novel series of compounds synthesised as the central theme of this project. Pharmacological characterisation of these new compounds aimed to resolve the importance of specific molecular interactions of their C3 substituent within the orthosteric binding pocket of CB1. Previous work showed the C3 carboxamide of rimonabant to be a molecular requirement for inverse agonism of CB1, with replacement by an alkene resulting in neutral antagonism. As a final extension to this study, eight ligands have been functionalised with a reactive tag with the aim of forming a covalent linkage to the receptor. This work aimed to clarify the exact site of ligand interaction within the GPCR, and provide an irreversible receptor labelling tool for receptor trafficking and location studies. Preliminary pharmacological assays to characterise affinity, functional activity, and possible covalent binding of these ligands were initiated. Nearly all of the novel molecular probes synthesised demonstrated high CB1 affinity. However, initial results from functional activity assays returned surprising data which suggests that the current understanding of molecular determinants for inverse agonism may not be entirely correct; Alleged neutral antagonist, VCHSR, reported by Hurst and Reggio, was observed in this study to have activity as an inverse agonist of CB1.3 Improved understanding of the structure-activity relationship of CB1 will inform ongoing development of cannabinoid drugs for therapeutic use in the treatment of illnesses ranging from obesity to Alzheimer’s disease.