The Cannabinoid CB1 Receptor (CB1R) is involved in a variety of physiological pathways
and has long been considered a golden target for therapeutic manipulation. A large body of evidence in
both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of
obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse
agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation,
displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting
in its eventual withdrawal from the European market. Several strategies are currently being pursued
to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally
restricted ligands, and allosteric modulators. In this review, we describe the progress in the development
of therapeutics targeting the CB1R in the last two decades.
Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats