Discovery of new CB2 cannabinoid receptor full agonists

Abstract

Cannabinoid CB2 receptor agonists have gained attention as potential therapeutic targets in the management of numerous diseases. Selectivity towards this receptor subtype is necessary to avoid the characteristic central side effects, mediated by CB1-activation. This project focused on the identification and optimization of novel selective cannabinoid CB2 receptor agonists. Initially, we projected and synthesized three new scaffold: 2,8-dioxo-1,2,3,4-tetrahydro-8H[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide; 8-oxo-1,2,3,4-tetrahydro-8H[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamides; 2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides. Obtained biological data led to structural modifications of the chemical scaffold and consequently discovery of a series of 7-oxo-[1,4]oxazino[2,3,4-ij]quinoline-6- carboxamide derivatives. Most of the newly synthesized compounds revealed great pharmacological profiles (0.32 nM < hKi CB2 < 98 nM). The effect of a chiral center on the biological activity was also investigated, and it resulted that the (R)-enantiomers showed greater affinity at the CB2 receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate assays, the novel series behaved as full agonists, exhibiting functional activity at the human CB2 receptor. Finally, compound 106, MT178, was analyzed in vivo to evaluate its antinociceptive efficacy on inflammatory and chronic pain animal models. MT178 produced strong analgesia in different pain models through selective activation of CB2 receptors.