Papahatjis D P, Kourouli T, Abadji V, Goutopoulos A, Makriyannis A
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Athens, Greece.
J Med Chem. 1998 Mar 26;41(7):1195-200. doi: 10.1021/jm970277i.
Accumulated evidence indicates that within the cannabinoid structure the aliphatic side chain plays a pivotal role in determining cannabimimetic activity. We describe the synthesis and affinities for the CB1 and CB2 receptors of a series of novel delta 8-THC analogues in which the side-chain pharmacophores are conformationally more defined than in the parent molecule. No analogue has the side-chain pharmacophore in a fully restricted conformation. However, our design serves to narrow down the scope of options for conformational requirements at the receptor active sites. All the analogues tested showed nanomolar or subnanomolar affinities for the receptors; 2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H- dibenzo[b,d]pyranyl)-2-hexyl-1,3-dithiolane was found to possess very high affinity for both cannabinoid receptors (CB1, Ki = 0.32 nM; CB2, Ki = 0.52 nM).
越来越多的证据表明，在大麻素结构中，脂肪族侧链在决定大麻素活性方面起着关键作用。我们描述了一系列新型δ8-四氢大麻酚（delta 8-THC）类似物的合成及其对CB1和CB2受体的亲和力，这些类似物的侧链药效基团在构象上比母体分子中的更明确。没有类似物的侧链药效基团处于完全受限的构象。然而，我们的设计有助于缩小受体活性位点构象要求的选择范围。所有测试的类似物对受体都表现出纳摩尔或亚纳摩尔的亲和力；发现2-(6a,7,10,10a-四氢-6,6,9-三甲基-1-羟基-6H-二苯并[b,d]吡喃基)-2-己基-1,3-二硫戊环对两种大麻素受体都具有非常高的亲和力（CB1，Ki = 0.32 nM；CB2，Ki = 0.52 nM）。
