Rimonabant redux and strategies to improve the future outlook of CB1 receptor neutral-antagonist/inverse-agonist therapies.

摘要

The endogenous cannabinoid (eCB) system plays a significant role in appetitive drive and feeding behavior. Therefore, antagonism of this receptor-mediated system was predicted to provide therapeutic benefit for the treatment of disorders associated with excess appetitive drive, such as obesity and substance abuse, as well as other disorders (1-3). Toward this end, cannabinoid receptor antagonists have been designed and investigated as pharmacotherapeutic agents. Rimonabant was the first-in-class of such compounds. Its biological activity is thought to be mediated by CB1 (cannabinoid receptor subtype 1) antagonist or inverse-agonist action, i.e., it acts as a functional antagonist in vivo. Rimonabant suppresses feeding in laboratory animals (4-6) and also shows efficacy at reducing body weight and improving cardiovascular and metabolic risk factors in nondiabetic and diabetic overweight and obese patients (7-10).