Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis

Selective
CB2 agonists represent an attractive therapeutic
strategy for the treatment of a variety of diseases without psychiatric
side effects mediated by the CB1 receptor. We carried out
a rational optimization of a black market designer drug SDB-001 that
led to the identification of potent and selective CB2 agonists.
A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles
resulted in potent CB2 antagonists (27 or 28, IC50 = 16–28 nM). Replacement of the
amidoalkyls from 3-position to the 2-position of the indole ring dramatically
increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed
a potent agonist activity on the CB2 receptor (EC50 = 114–142 nM) without observable agonist or antagonist activity
on the CB1 receptor. Furthermore, 57 significantly
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.