KLS-13019, a novel structural analogue of cannabidiol (CBD) and GPR55 receptor antagonist, Prevents and Reverses Chemotherapy-Induced Peripheral Neuropathy (CIPN) in Rats

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol (CBD) structural analogue and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once daily 1mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for one week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7-10 in a chronic dosing paradigm and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to pre-paclitaxel injection baseline levels with both I.P. and P.O. administration after acute dosing. In the chronic dosing paradigm, 4 consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control Animals. Additionally, co-administration of KLS -13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain. Significance Statement Chemotherapy-induced neuropathic pain (CIPN) is a common, debilitating side effect of Cancer treatment with no known cure. GPR55 Antagonist KLS-13019 represents a novel class of drug for this condition that is a potent, durable inhibitor of allodynia associated with CIPN in rats in both prevention and reversal dosing paradigms. This novel therapeutic approach addresses a critical area of unmet medical need.

Orphan GPCRs; behavioral pharmacology; cancer chemotherapy; cannabinoids; g protein-coupled receptors (GPCRS); neurogenic pain.