CB₁ receptor antagonists: new discoveries leading to new perspectives

Abstract

CB(1) receptor antagonists were among the most promising drug targets in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems; however, use of rimonabant, the first marketed CB(1) receptor antagonist, has been suspended because of its anxiogenic and depressogenic side effects. Because some other antiobesity drugs, like dexfenfluramine or sibutramine, were also suspended, the unmet need for drugs that reduce body weight became enormous. One approach that emerged was the use of CB(1) receptor antagonists that poorly cross the blood brain barrier, the second, the development of neutral antagonists instead of inverse agonists, and the third, use of personalized medicine, namely the selection of the patient population without psychiatric side effects. In this review, we dissect the peripheral and central mechanisms involved in the effects of CB(1) receptor antagonists and argue that central mechanisms are more or less involved in most cardiometabolic therapeutic effects and thus, among patients with unsatisfactory therapeutic response to compounds with peripheral action, centrally acting antagonists may be needed. An analysis of pharmacogenetic factors may help to identify persons who are at no or low risk for psychiatric adverse effects. Here, we present the models and identify molecular mechanisms and receptors involved in the effects of stress-, anxiety- and depression-related neurocircuitries sensitive to CB(1) receptor antagonists, like the serotonergic, noradrenergic and dopaminergic systems, which are not only regulated by CB(1) receptors, but also regulate the synthesis of the endocannabinoid 2-arachidonoyl-glycerol.

Metabolic effects of smoking cessation

“…The idea of treating tobacco dependence and obesity together is a provocative one. Rimonabant, a cannabinoid receptor antagonist, has been used to treat obesity 96 and nicotine dependence 97 , and is also effective against the metabolic syndrome 98 . However, rimonabant had adverse psychiatric effects and did not receive FDA approval 96 .…”

Pyrazoles with a “click” 4-[N-(4-fluorobutyl)-1,2,3-triazole] substituent in position 3 are nanomolar CB1 receptor ligands

“…The reaction was cooled down to r.t., poured into water, extracted with DCM, dried over MgSO 4 , filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (Hexane/EtOAc 6:4) to give the desired compound 1a-c. 2,123.1,125.8,127.9,128.0,128.3,129.0,129.2,129.7,130.2,130.4,131.1,133.6,134.0,135.9,136.5,136.8,137.3,142.5,143.9,146.2;MS (ESI) 8,83.2 (d,115.5,120.7,123.6,124.2,125.0,127.9 (2C),129.0,130.2,131.1,134.0,136.0,136.3,136.5,137.1,139.3,142.4,143.9,146. = 5.7 Hz),1H),6.73 (d,1H,J = 3.8 Hz),6.82 (d,1H,J = 3.8 Hz),7.34 (dd,1H,J = 2.2,8.5 Hz),7.40 (d,1H,J = 8.5 Hz),7.50 (d,…”

“…CB 1 receptors are localised predominantly in the brain [2] whereas CB 2 receptors are more abundant in peripheral nervous system (PNS) cells [3], although some studies have shown the presence of CB 1 in the PNS [4] and of CB 2 in the central nervous system, albeit in low density [5]. CB 1 receptors have been associated with a number of disorders, including depression [6], anxiety [7], stress [8], schizophrenia [9], chronic pain [10] and obesity [11]. For this reason, several cannabinoid ligands were developed as drug candidates.…”

A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents

“…Ability of neutral antagonists 'not to affect whole gut transit' may be a key for the future development of CB1 receptor antagonists [10]. Kirilly et al [30] have reviewed the adverse effects associated with the peripheral acting CB1 receptor antagonists like gastrointestinal disorders such as nausea, vomiting, diarrhea and dyspepsia, and nervous system disorders such as dizziness, vertigo and hypesthesia and other events like fatigue, hot flush, tendonitis and contusion. There are evidences indicating the existence of allosteric binding sites on CB1 receptors [31].…”