Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis

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• 作者：Paula Morales ; María Gómez-Cañas ; Gemma Navarro ; Dow P. Hurst ; Francisco J. Carrillo-Salinas ; Laura Lagartera ; Ruth Pazos ; Pilar Goya ; Patricia H. Reggio ; Carmen Guaza ; Rafael Franco ; Javier Fernández-Ruiz ; Nadine Jagerovic
• 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：6753-6771
• 全文大小：896K
• 年卷期：0
• ISSN：1520-4804

文摘

A combination of molecular modeling and structure–activity relationship studies has been used to fine-tune CB₂ selectivity in the chromenopyrazole ring, a versatile CB₁/CB₂ cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies, and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB₂ agonist isoxazole derivative, was tested in the acute phase of Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.