Drake D J, Jensen R S, Busch-Petersen J, Kawakami J K, Concepcion Fernandez-Garcia M, Fan P, Makriyannis A, Tius M A
Department of Chemistry, University of Hawaii, 2545 The Mall, Honolulu, Hawaii 96822, USA.
J Med Chem. 1998 Sep 10;41(19):3596-608. doi: 10.1021/jm960677q.
The stereoelectronic requirements for interaction of the southern aliphatic hydroxyl of cannabimimetic pharmacophores with the CB1 and CB2 receptors are explored. The stereoselective syntheses of three series of classical/nonclassical hybrid cannabinoids are described. These compounds were designed to investigate the importance of the southern aliphatic hydroxyl (SAH) pharmacophore for cannabimimetic activity. Variation in the chain length of the SAH moiety in these 6beta-(hydroxyalkyl)dihydrobenzopyran analogues, from 6beta-hydroxymethyl to 6beta-(omega-hydroxyethyl) and 6beta-(omega-hydroxypropyl), and the effects of replacing the hydroxyl functionality by hydride and iodide are reported. Our results indicate that the SAH pharmacophore has less pronounced effects than the C-3 aliphatic chain on cannabinoid activity. Furthermore, it appears that this southern molecular component is capable of interacting with two different subsites on the receptor and that the nature of this interaction is determined by the terminal substituent on the C-6beta alkyl group. One of the subsites can accommodate the relatively polar SAH pharmacophore, while the second subsite interacts with more hydrophobic C-6beta substituents and can accommodate large spherical pharmacophores separated by three methylene carbons from the tricyclic cannabinoid template.
探索了大麻模拟药效基团的脂肪族羟基与CB1和CB2受体相互作用的立体电子要求。描述了三个系列经典/非经典杂交大麻素的立体选择性合成。设计这些化合物是为了研究脂肪族羟基（SAH）药效基团对大麻模拟活性的重要性。报道了这些6β-（羟烷基）二氢苯并吡喃类似物中SAH部分链长的变化，从6β-羟甲基到6β-（ω-羟乙基）和6β-（ω-羟丙基），以及用氢化物和碘化物取代羟基官能团的影响。我们的结果表明，SAH药效基团对大麻素活性的影响不如C-3脂肪族链明显。此外，似乎这个分子的南部成分能够与受体上的两个不同亚位点相互作用，并且这种相互作用的性质由C-6β烷基上的末端取代基决定。其中一个亚位点可以容纳相对极性的SAH药效基团，而第二个亚位点与疏水性更强的C-6β取代基相互作用，并且可以容纳与三环大麻素模板由三个亚甲基碳隔开的大的球形药效基团。
