The therapeutic potential of second and third generation CB1R antagonists

Publication date: Available online 9 January 2020Source: Pharmacology & TherapeuticsAuthor(s): Resat Cinar, Malliga R. Iyer, George KunosAbstractEndocannabinoids acting via CB1 receptors (CB1R) play a critical role in regulating energy homeostasis, which was the rationale for the pharmaceutical development of CB1R antagonists for the treatment of obesity. Although the first-in-class CB1R antagonist rimonabant proved to be effective in mitigating obesity and its multiple cardiometabolic complications, it was withdrawn from clinical use due to CNS-mediated neuropsychiatric side effects, which halted the further therapeutic development of the whole class of these compounds. Compared to the brain, CB1Rs are expressed at low yet functional levels in peripheral organs involved in regulating energy homeostasis, including liver, skeletal muscle, adipose tissue and endocrine pancreas. In recent preclinical studies, selective targeting of these receptors by ‘second generation’ peripherally restricted CB1R antagonists replicated the metabolic benefits of rimonabant in rodent models of obesity and diabetes without causing CNS-mediated side effects. Increased CB1R activity also contributes to complex, multifactorial disorders such as various forms of tissue fibrosis, treatment of which may benefit from simultaneous engagement of more than one therapeutic target. Accordingly, novel ‘third generation’ hybrid inhibitors of peripheral CB1R and inducible NO synthase were tested in mous...

Source: Pharmacology and Therapeutics - January 9, 2020 Category: Drugs & Pharmacology Source Type: research