New role of phenothiazine derivatives as peripherally acting CB1 receptor antagonizing anti-obesity agents

Abstract

Developing peripherally active cannabinoid 1 (CB1) receptor antagonists is a novel therapeutic approach for the management of obesity. An unusual phenothiazine scaffold containing CB1R antagonizing hit was identified by adopting virtual screening work flow. The hit so identified was further modified by introducing polar functional groups into it to enhance the polar surface area and decrease the hydrophobicity of the resulting molecules. CB1 receptor antagonistic activity for the designed compounds was computed by the previously established pharmacophore and three dimensional quantitative structure–activity relationship models. Docking studies of these designed compounds confirmed the existence of favourable interactions within the active site of the CB1 receptor. The designed compounds were synthesized and evaluated for their CB1 receptor antagonistic activity. Parallel artificial membrane permeability assay was performed to evaluate their potential to permeate into the central nervous system wherein it was observed that the compounds did not possess the propensity to cross the blood brain barrier and would be devoid of central nervous system side effects. In pharmacological evaluation, the synthesized compounds (23, 25, 27 and 34) showed significant decrease in food intake suggesting their potential application in the management of obesity through CB1 receptor antagonist activity.

Causes and solutions to “globesity”: The new fa(s)t alarming global epidemic

“…The first selective CB1 receptor antagonist approved to treat obesity was rimonabant which was withdrawn shortly after its introduction to the European market, because independent reports suggested serious adverse events, including severe depression and suicidal thoughts (Cheung et al, 2013). Recent study examined the weight loss potential of new generation CB1 antagonists designed to selectively bind the peripheral receptors, but not to penetrate the blood-brain barrier and thus to avoid the behavioral effects of the centrally active agents (Sharma et al, 2018).…”

Advances in Patented CB1 Receptor Antagonists for Obesity

“…Compounds with <60Å polar surface area could easily penetrate the blood-brain barrier. So, efforts are being made to design compounds having more polar surface area so that a compound is restricted to the peripheral region only abolishing the CNS side effects [5].…”

“…Patented CB1 receptor antagonists CB1 receptor antagonists discovered in the last one decade have been patented by different groups namely, Jenrin Discovery (PA, USA), Sanofi-Aventis, Solvay Pharmaceuticals, Green Cross Corporation (South Korea), Mitsubishi Tanabe Pharma (Japan), Merck and Co. (NJ, USA), Merck Sharp & Dohme Corp., 7TM Pharma (Denmark), Eli Lilly and Company (IN, USA), Schering Corp. (NJ, USA), University of Connecticut (CT, USA), Amorepacific Corporation (Seoul, South Korea) and AstraZeneca AB (UK). These groups have patented compounds having azetidine, azulene, imidazole, immidazoline, morpholine, piperazine, pyrrole, pyrazole, pyrazoline, pyrrolidine, pyridine, pyrimidine, purine, thiophene and triazole scaffolds [5,10]. Some important compounds from each category are highlighted in the following sections.…”

“…Thus, efforts are being made for the discovery of novel anti-obesity agents with improved efficacy and safety profile.Rimonabant, a selective CB1 endocannabinoid receptor antagonist, developed by Sanofi-Aventis (Paris, France) as Acomplia R was first approved for the European market in the year 2006 for the treatment of obesity, but it had to be withdrawn within a span of 2 years due to its psychiatric side effects. On 8 October 2010, Abbott Laboratories (IL, USA) announced withdrawal of sibutramine, a dual serotonin-norepinephrine reuptake inhibitor from the US market due to its increased risk of adverse cardiovascular events and low efficacy [5].…”

The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows Reduced Fear-Promoting Effects in Mice

“…Despite this experience, there is still interest in the development of CB1 antagonism as a pharmacological tool for the treatment of metabolic disorders, however, with a better safety profile ( Le Foll et al., 2009 ; Janero et al., 2011 ; Ward and Raffa, 2011 ; Kirilly et al., 2012 ). In this context, two main alternatives are currently discussed: (1) the use of CB1 neutral antagonist, such as AM4113, NESS0327, or AM6545, instead of the CB1 receptor antagonists/inverse agonists (e.g., rimonabant), which have recently shown efficacy to reduce body weight and food intake in rodents with less unwanted side effects than rimonabant ( Sink et al., 2008 , 2010a , b ; Meye et al., 2013 ; Gueye et al., 2016 ) and (2) the use of peripherally directed CB1 inverse agonist/antagonist, which revealed promising preclinical results to reduce body weight ( Tam et al., 2012 , 2018 ; Chorvat, 2013 ; Sharma et al., 2018 ). Among them, TM38837 was shown to induce a significant weight loss in obese mice similarly to rimonabant ( Noerregaard et al., 2010 ), with no clear central nervous system (CNS) effects and a potential favorable side effects profile ( Klumpers et al., 2013 ), possibly because of reduced brain CB1 receptor occupancy ( Takano et al., 2014 ).…”