Axially Chiral Cannabinols: A New Platform for Cannabinoid-Inspired Drug Discovery.
Axially Chiral Cannabinols: A New Platform for Cannabinoid-Inspired Drug Discovery.
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DOI：
10.1002/cmdc.202000025
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发表时间：
2020-05-06
期刊：
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
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植物大麻素（及其合成类似物）在现代医学中作为有前途的先导物而受到极大的关注。考虑到这一点，设计植物大麻素启发分子的新方向是直接感兴趣的。在这方面，我们假设轴向手性大麻酚（ax-CBNs），大麻酚（CBN）的非天然和未知异构体可能是大麻素启发药物发现的有价值的支架。有两个主要因素引导我们对这些支架的兴趣：(a) ax- cbn将具有基态三维；配体与受体的相互作用在互补的3d拓扑下更为显著，并且(b)其核心结构的ax-CBNs是联芳基分子，由于其易于功能化和稳定性，通常是药物开发的有吸引力的平台。在此，我们报道了ax-CBN的合成，实验和计算检查了物理性质，并在小鼠行为研究中对ax-CBN和THC进行了比较分析。大麻素研究的新进展。我们报告的策略构象偏向大麻酚（CBN）支架在三维取向。CBN C-9到C-10甲基转位产生轴手性大麻酚（ax-CBNs）， CBN的非天然异构体，由药学上相关的联芳基框架组成，由于空间位阻显示基态三维。构象偏向支架可能为大麻素激发的药物发现提供新的方向。
Phytocannabinoids (and synthetic analogs thereof) are gaining significant attention as promising leads in modern medicine. Considering this, new directions for the design of phytocannabinoid-inspired molecules is of immediate interest. In this regard, we have hypothesized that axially-chiral-cannabinols (ax-CBNs), unnatural and unknown isomers of cannabinol (CBN) may be valuable scaffolds for cannabinoid-inspired drug discovery. There are two main factors directing our interest to these scaffolds: (a) ax-CBNs would have ground-state three-dimensionality; ligand–receptor interactions can be more significant with complimentary 3D-topology, and (b) ax-CBNs at their core structure are biaryl molecules, generally attractive platforms for pharmaceutical development due to their ease of functionalization and stability. Herein we report a synthesis of ax-CBNs, examine physical properties experimentally and computationally, and perform a comparative analysis of ax-CBN and THC in mice behavioral studies. A new twist for cannabinoid research. We report a strategy to conformationally bias cannabinol (CBN) scaffolds in a three-dimensional orientation. CBN C-9 to C-10 methyl transposition yields axially-chiral cannabinols (ax-CBNs), unnatural isomers of CBN that are comprised of the pharmaceutically relevant biaryl framework and display ground state three-dimensionality due to steric hinderance. The conformationally biased scaffolds may provide new directions for cannabinoid-inspired drug discovery.
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DOI：
10.4137/pmc.s32171
发表时间：
2016
期刊：
Perspectives in medicinal chemistry
影响因子：
--
作者：
Bow EW;Rimoldi JM
通讯作者：
Rimoldi JM
影响因子：
5.6
作者：
Devinsky O;Cilio MR;Cross H;Fernandez-Ruiz J;French J;Hill C;Katz R;Di Marzo V;Jutras-Aswad D;Notcutt WG;Martinez-Orgado J;Robson PJ;Rohrback BG;Thiele E;Whalley B;Friedman D
通讯作者：
Friedman D
影响因子：
1.8
作者：
GODFREY, JD;MUELLER, RH;COLANDREA, VJ
通讯作者：
COLANDREA, VJ
影响因子：
7.3
作者：
Dixon, Darryl D.;Sethumadhavan, Divakaramenon;Makriyannis, Alexandros
通讯作者：
Makriyannis, Alexandros
影响因子：
3.6
作者：
Minuti, Lucio;Temperini, Andrea;Ballerini, Eleonora
通讯作者：
Ballerini, Eleonora