作为大麻素受体调节剂的新型 Machaeriol 类似物：(+)-六氢大麻素的结构-活性关系及其同种型选择性,ACS Omega

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作为大麻素受体调节剂的新型 Machaeriol 类似物：(+)-六氢大麻素的结构-活性关系及其同种型选择性
ACS Omega ( IF 3.7 ) Pub Date : 2021-07-28 , DOI: 10.1021/acsomega.1c02413
Saqlain Haider ₁ , Pankaj Pandey ₁ , Chada Raji Reddy ₂ , Janet A Lambert ₃ , Amar G Chittiboyina ₁

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Machaeriols 是一类重要的化合物，其结构类似于四氢大麻酚 (Δ ⁹ -THC)，主要区别在于环连接处的立体化学倒转为 [6a R , 10a R] 以及由于饱和而在 A 环的 C9 位置处的额外立体中心。之前的一项研究报告称，machaeriols 没有表现出任何大麻素受体活性，即使这些六氢二苯并吡喃类似物模拟了特权 (+)-四氢大麻素支架。为了解开调节大麻素受体的结构必要条件，采用了一种简单的后期发散方法来使用 Suzuki 偶联反应对 machaeriol 支架进行功能化。合成了十四种六氢类似物，并针对大麻素受体同种型 CB ₁和 CB ₂进行了筛选。有趣的是，许多类似物对两种受体都显示出显着的结合亲和力。然而，两个类似物，11H和11J,在 GTPγS 测定中被鉴定为具有 CB ₂受体选择性功能活性；它们被发现是微摩尔范围的激动剂，EC ₅₀值分别为 5.7 和 16 μM。此外，CB ₂受体和两种新型类似物之间的分子动力学模拟通过紧紧占据 CB ₂受体的活性配体结合域并保持与关键残基 Phe94、Phe281 和 Ser285 的稳定相互作用，产生了独特的相互作用特征。首次借助（+）-六氢大麻素的构效关系，CB ₂使用钯介导的 C-C 键形成的后期多样化鉴定了选择性激动剂。通过简单地切换到 ( R )-香茅醛作为手性前体，可以使用当前的合成方法获得具有更好 CB ₁ /CB ₂受体异构体选择性的对映异构纯的 (-)-六氢大麻素。

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Novel Machaeriol Analogues as Modulators of Cannabinoid Receptors: Structure–Activity Relationships of (+)-Hexahydrocannabinoids and Their Isoform Selectivities

Machaeriols are an important class of compounds that structurally resemble tetrahydrocannabinol (Δ⁹-THC), with the major differences being inverted stereochemistry at the ring junction as [6aR, 10aR] and an additional stereocenter at the C9 position of the A-ring due to saturation. A previous study reported that machaeriols did not show any cannabinoid receptor activity, even though these hexahydrodibenzopyran analogues mimic a privileged (+)-tetrahydrocannabinoid scaffold. To unravel structural requisites for modulation of cannabinoid receptors, a simple late-stage divergent approach was undertaken to functionalize the machaeriol scaffold using the Suzuki coupling reaction. Fourteen hexahydro analogues were synthesized and screened against both cannabinoid receptor isoforms, CB₁ and CB₂. Interestingly, many of the analogues showed a significant binding affinity for both receptors; however, two analogues, 11H and 11J, were identified as possessing CB₂ receptor-selective functional activity in the GTPγS assay; they were found to be micromolar-range agonists, with EC₅₀ values of 5.7 and 16 μM, respectively. Furthermore, molecular dynamics simulations between the CB₂ receptor and two novel analogues resulted in unique interaction profiles by tightly occupying the active ligand-binding domain of the CB₂ receptor and maintaining stable interactions with the critical residues Phe94, Phe281, and Ser285. For the first time, with the aid of structure–activity relationships of (+)-hexahydrocannabinoids, CB₂ selective agonists were identified with late-stage diversification using palladium-mediated C–C bond formation. By simply switching to (R)-citronellal as a chiral precursor, enantiomerically pure (−)-hexahydrocannabinoids with better CB₁/CB₂ receptor isoform selectivity can be obtained using the current synthetic approach.

更新日期：2021-08-10

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