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

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 attrac...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (4), p.1619-1624
Hauptverfasser: 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.
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Sprache:eng
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Zusammenfassung: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.12.124