化学
大麻素
阿托品
大麻素受体
大麻酚
大麻酚
轴手性
立体化学
内大麻素系统
组合化学
对映选择合成
受体
生物化学
兴奋剂
心理学
催化作用
精神科
大麻
作者
Sara E. Kearney,Anghelo Gangano,Daniel Gadsden Barrus,Kyle J. Rehrauer,Terry-Elinor Reid,Primali V. Navaratne,Emily K. Tracy,Adrián E. Roitberg,Ion Ghiviriga,Christopher W. Cunningham,Thomas F. Gamage,Alexander J. Grenning
摘要
The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics targeting the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an additional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This unique structural modification is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ushering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug development. In this full report, we describe the philosophy guiding the design of axCBNs as well as several synthetic strategies for their construction. We also introduce a second class of axially chiral cannabinoids inspired by cannabidiol (CBD), termed axially chiral cannabidiols (axCBDs). Finally, we provide an analysis of axially chiral cannabinoid (axCannabinoid) atropisomerism, which spans two classes (class 1 and 3 atropisomers), and provide first evidence that axCannabinoids retain─and in some cases, strengthen─affinity and functional activity at cannabinoid receptors. Together, these findings present a promising new direction for the design of novel cannabinoid ligands for drug discovery and exploration of the complex endocannabinoid system.
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