the U.S. continues to face an unprecedented opioid public health crisis that has resulted in tremendous morbidity and mortality, as well as a significant cost to society, which has been further exacerbated by the on-going COVID- 19 pandemic. Continual, heavy reliance on opioids to treat chronic pain has been a major contributor to this major problem. Here, we propose to develop non-addictive analgesics that lack the deleterious side effects associated with opioids using a new strategy that targets allosteric sites of the cannabinoid CB1 receptor. While CB1 receptor activation by orthosteric agonists, such as delta-9-tetrahydrocannabinol (THC), produces potent antinociceptive effects in a wide range of pain models, these drugs also elicit unwanted cannabimimetic side effects as well as abuse and dependence liability. In contrast, CB1 receptor positive allosteric modulators (PAMs) offer promise of therapeutic gain to treat pain with substantially diminished risk of cannabimimetic, abuse, and dependence effects. Early generation CB1 PAMs showed promising antinociceptive effects in preclinical models of pathological pain without inducing CNS adverse effects or resulting in tolerance or dependence following repeated administration; however, the structures of these ligands presented pitfalls for drug discovery and development. Thus, our laboratories have produced a novel class of CB1 PAMs in which the lead compound induces robust CB1 allosteric activation and provides a novel scaffold to increase pharmacological design flexibility to provide enhanced druggability and antinociceptive efficacy without cannabimimetic side effects and abuse/dependence liability. The UG3 phase contains three specific aims. Studies in Aim 1 optimize novel CB1 PAMs, verify target engagement, and conduct pharmacokinetic and metabolic stability studies. In Aim 2, we will evaluate CB1 PAMs in mouse models of pain versus cannabimimetic side effects, abuse liability, and dependence liability. In Aim 3 (UG3 phase). Aim 3 will investigate miRNA as potential biomarkers for allosterically activated CB1 receptors. Finally, aim 4 in the UH3 phase will pursue IND-enabling studies towards drug development. The goal of this project is to advance a selected CB1 PAM in preclinical studies as a non-addictive, non-opioid analgesic to treat chronic pain and support future IND clinical investigation.
