New Drugs, New Biology, Tomorrow’s Therapies: Design and Characterisation of Novel Cannabinoid Ligands

Compounds derived from Cannabis sativa, termed “cannabinoids”, primarily exert their effects via two G protein-coupled receptors (GPCRs), Cannabinoid Receptors 1 and 2 (CB1 and CB2). Both receptors are under intense scrutiny as potential therapeutic targets.

Clinical development of CB1-targeted drugs has been hindered by CB1’s high level of central nervous system expression which mediates Cannabis’ psychotropic effects. We are interested in avoiding these side-effects by developing ligands which activate more limited or unique signalling patterns in comparison with traditional cannabinoid ligands, and/or whose physicochemical properties reduce the passage of drug into the central nervous system.

On the other hand, CB2 is expressed primarily in the immune system and CB2-targeted drugs are promising therapeutic leads in a wide range of disorders involving immune system dysregulation, including multiple sclerosis, autoimmune disorders, atherosclerosis, stroke and inflammatory bowel disease.

We are collaborating with researchers at the University of Otago in developing novel cannabinoid ligands which we anticipate may represent new therapeutic leads and/or pharmacological tools.

The focus of this project will be to screen novel cannabinoids (and previously reported cannabinoids of interest) for their properties in various aspects of their molecular pharmacology at CB2, and follow up leads of interest to probe further into the functional effects and mechanisms driving these.

We are particularly interested in studying functional selectivity, wherein a single GPCR has the potential to mediate the activation or inactivation of diverse signalling pathways and each molecule that interacts with the receptor has the potential to induce a unique ‘fingerprint’ of signalling events within the cell. A cutting-edge concept in functional selectivity is that of spatio-temporal modulation, and this project will characterise ligand function in this context by utilising cutting-edge spatially restricted signalling pathway biosensors.

This project would primarily be based at the University of Auckland though may include spending some time at the University of Otago carrying out chemical synthesis. The structure and specifics of this can somewhat be tailored to the background and interests of the candidate.