Project 3 - In vivo pharmacology of cannabinoid receptor probes

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Project Summary The therapeutic potential of the endocannabinoid system has yet to translate into safe and effective medicines. The translation gap, or “valley of death” separates promising preclinical research from identification of a newly approved drug. Functional selectivity (or biased agonism) is a recently appreciated property of CB1 and CB2 receptor signalling. Challenges for clinical translation include the question of what signalling pathway best predicts therapeutic efficacy. It is, therefore, necessary to establish that candidate ligands engage the specific signalling pathways necessary for therapeutic benefit, while, ideally, circumventing those pathways responsible for unwanted side effects. Both biased agonism and allosteric modulation represent alternative strategies to harness the therapeutic potential of the endocannabinoid signalling system without the unwanted effects of direct acting CB1 agonists. The signalling pathways necessary and dispensable for CB1 and CB2 therapeutic efficacy remain poorly understood. Bridging this gap in knowledge is critical if we are to avoid costly failures in clinical translation. Project 3 will use novel CB1 and CB2 probes that are developed in Project 1 and characterized in vitro in Project 2 to elucidate how CB1 biased agonism, probe specific CB1 positive allosteric modulation and CB2 selective agonism impact in vivo pharmacology. Aim 1 will define the in vivo pharmacology of functionally selective CB1 probes. We will profile functionally selective CB1 agonists as well as tight binding (slow Koff) and probe-specific CB1 PAMs (that exhibit high potency in our preliminary in vivo studies) for cardinal signs of CB1 activation, ability to suppress neuropathic nociception as well as propensity to induce tolerance and physical dependence. Aim 2 will define the in vivo pharmacology of CB2 agonists with improved selectivity for CB2 over CB1. We will ascertain whether in vivo pharmacological profiles and selectivity can be improved by incorporating high affinity CB2 agonism with a lack of CB1 agonism. We will also determine whether in vivo pharmacological profiles can be enhanced by incorporating CB1 antagonism (neutral, inverse agonism, partial agonism) with high affinity CB2 agonism. This Aim will compare a spectrum of ligands exhibiting these properties for cannabimimetic effects, anti-allodynic efficacy and tolerance, as well as capacity to induce physical dependence and negative affective states. This project will validate improved CB1 and CB2 probes, not to develop a medication. Elucidation of signalling pathways necessary and dispensable for in vivo efficacy and unwanted side effects will improve cannabinoid-based therapeutics and break down barriers to successful clinical translation.