Although marijuana is currently legal for both recreational and medical purposes in Canada and some U.S. states, abuse of synthetic cannabinoids initially developed as research tools to investigate the endogenous cannabinoid system remains a serious public health issue. These aminoalkylindole derivatives, as exemplified by SDB-001, bind to both CB1 and CB2 receptors and exert cannabimimetic effects similar to (−)-trans-Δ9-tetrahydrocannabinol, the main psychoactive component present in the cannabis plant. Since CB1 receptor ligands were found to have severe adverse psychiatric effects, increased attention was turned to exploiting the potential therapeutic value of the CB2 receptor. Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases including autoimmune diseases. In our efforts to discover novel and selective CB2 receptor agonists, a black-market designer drug SDB-001 was selected as a starting point for lead compound identification. Indole carboxamides and pyrazole carboxamides were thus designed, synthesized, and biologically evaluated. Systematic structure−activity relationship investigations resulted in the identification of promising selective CB2 receptor agonists, indole-2-carboxamide 57, which dramatically alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. More recently, pyrazole-3-carboxamide 66 with improved PK profiles, was prove to significantly attenuate dermal inflammation and fibrosis in a bleomycin-induced mouse model of systemic sclerosis. Collectively, our data support that CB2 receptor agonists might serve as potential therapeutics for treating a series of autoimmune diseases.

From designer drug to the discovery of selective cannabinoid type 2 receptor agonists for the treatment of autoimmune diseases

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.