Development of non-opioid, non-addictive analgesics for treating neuropathic pain

Project Summary Safe and effective treatment of neuropathic pain remains a challenging medical problem. First- and second-line treatments show modest, variable efficacies in treating neuropathic pain and carry serious liabilities. Orthosteric CB1R agonists like delta-9-tetrahydrocannabinol show (pre)clinical efficacy in suppressing neuropathic nociception but also produce unwanted side-effects (e.g., tolerance, physical dependence, psychoactivity). CB2R agonists (GW842166X, S-777469, and JBT-101) have not shown efficacy in clinical trials in other indications and have not been tested for efficacy in people in therapeutic indications supported by the preclinical literature. We have successfully identified novel “dualsteric modulators” having a unique pharmacological phenotype characterized by activity as both a non-psychoactive cannabinoid CB1R allosteric agonist-positive allosteric modulator (ago-PAM) and a CB2R agonist. Our central hypothesis is that such dualsteric ligands leverage the therapeutic advantages of allosteric GPCR regulation of both cannabinoid receptors and provide effective broad-spectrum analgesia without abuse liability and other CB1R-mediated side effects. We will unite the complementary and non-overlapping expertise of five different laboratories to conduct experiments proposed under three Specific Aims. Aim1 will design and synthesize a series of novel N-arylindole and 2-cycyloalkyllindole analogs as CB1R/CB2R ago-PAMs with improved pharmacological profiles compared to our lead compounds, GAT1102 and GAT588. Aim 2 will perform in vitro pharmacological characterization and target-engagement studies and in vivo ADME/PK profiling of key CB1R/CB2R ago-PAMs to eliminate potential liabilities and identify compounds with suitable drug-like properties for in vivo studies. Aim 3 will perform in vivo evaluation of optimized CB1R/CB2R ago-PAMs with suitable drug-like properties for suppressing nociception in mechanistically distinct neuropathic pain states. We postulate that our dualsteric ligands will suppress both sensory and negative affective dimensions associated with neuropathic nociception without unwanted side effects of orthosteric CB1 agonists. Successful validation of our innovative first-in-class therapeutic strategy offers the potential to change the face of pain management.