Grant: Project Grant

Endocannabinoids are produced in neurones and interact with cannabinoid CB1 receptors to modulate a range of behaviours, including mood; the system can be over-active or underactive in certain diseases. The endocannabinoids interact with the cannabinoid CB1 receptor. In 2005, we produced the first evidence that the cannabinoid CB1 receptor contains an allosteric binding site. CB1 allosteric modulators have therapeutic potential with the advantage of only turning up or down an inappropriately balanced endocannabinoid system, rather than affecting normal physiological function. Recently, we have generated a novel CB1 allosteric modulators, that display more drug like characteristics. These compound have an unusual pharmacological profile, blocking some of the downstream effects of CB1 receptor activation. This unique profile has the potential to offer advantages over previous molecules that target the CB1R. Our preliminary studies also indicate our novel CB1 allosteric modulators are highly effective in reducing the behavioural phenotypes in two distinct mouse behavioural models of hyperdopamine states that are related to schizophrenia (SCZ) and bipolar disorder (BD). Endocannabinoid levels and CB1 receptors are dysregulated in schizophrenia. Taken together, the data suggest that the endocannabinoid system may be a target for the development of new therapeutics for the treatment for psychosis and mania. Here we will characterize the unique pharmacology displayed by our new molecules. We will develop novel analogues that are further optimized for clinical development. Finally, we will examine the effects of our compounds on behaviours in two distinct animal models of hyperdopamine and models of liver injury. This program will allow us to develop, pharmacologically characterize and optimize a unique new class of CB1 molecules to determine the therapeutic potential to facilitate translation in the clinic.