γ-Carbolines: A novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration

• Published in: Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (4), p.1619-1624
• Main Authors: Cheng, Yun-Xing, Pourashraf, Mehrnaz, Luo, Xuehong, Srivastava, Sanjay, Walpole, Christopher, Salois, Dominic, St-Onge, Stephane, Payza, Kemal, Lessard, Etienne, Yu, Xiao Hong, Tomaszewski, Mirosław J.
• Format: Article
• Language: English
• Subjects: adverse effects; agonists; analgesic effect; Analgesics; Analgesics - chemistry; Analgesics - metabolism; Analgesics - pharmacology; Animal models; Animals; Biological and medical sciences; Brain; Brain - drug effects; Brain - metabolism; Cannabinoid; Cannabinoid CB1 receptors; Cannabinoid CB2 receptors; cannabinoids; Cannabinoids - agonists; Carbolines; Carbolines - chemistry; Carbolines - metabolism; Carbolines - pharmacology; Cell Line; Central nervous system; Chronic pain; Drug addictions; Drug Stability; Humans; Inflammation; Medical sciences; Molecular Structure; Pain; Pain - drug therapy; Pharmacology. Drug treatments; Physicochemical properties; Rats; risk; Risk factors; Side effects; Solubility; Toxicology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.124

An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.