Novel C-Ring-Hydroxy-Substituted Controlled Deactivation Cannabinergic Analogues

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• 作者：Shashank Kulkarni ; Spyros P. Nikas ; Rishi Sharma ; Shan Jiang ; Carol A. Paronis ; Michael Z. Leonard ; Bin Zhang ; Chandrashekhar Honrao ; Srikrishnan Mallipeddi ; Jimit Girish Raghav ; Othman Benchama ; Torbjörn U. C. Järbe ; Jack Bergman ; Alexandros Makriyannis
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 28, 2016
• 年：2016
• 卷：59
• 期：14
• 页码：6903-6919
• 全文大小：692K
• 年卷期：0
• ISSN：1520-4804

文摘

In pursuit of safer controlled-deactivation cannabinoids with high potency and short duration of action, we report the design, synthesis, and pharmacological evaluation of novel C9- and C11-hydroxy-substituted hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC) analogues in which a seven atom long side chain, with or without 1′-substituents, carries a metabolically labile 2′,3′-ester group. Importantly, in vivo studies validated our controlled deactivation approach in rodents and non-human primates. The lead molecule identified here, namely, butyl-2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]-2-methylpropanoate (AM7499), was found to exhibit remarkably high in vitro and in vivo potency with shorter duration of action than the currently existing classical cannabinoid agonists.