Busch-Petersen J, Hill W A, Fan P, Khanolkar A, Xie X Q, Tius M A, Makriyannis A
Department of Chemistry, University of Hawaii, Honolulu 96822, USA.
J Med Chem. 1996 Sep 13;39(19):3790-6. doi: 10.1021/jm950934b.
The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain, we synthesized a series of cannabinoids in which rotation around the C1'-C2' bond is blocked. The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific introduction of the beta-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (Ki = 0.89 nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-beta-11-hydroxyhexahydrocannabinol was the least potent binding to CB1 (Ki = 8.9 nM) and had the lowest selectivity between CB1 and CB2.
大麻素侧链是大麻素与其受体（CB1和CB2）相互作用中的关键药效基团。为了研究侧链的立体化学要求，我们合成了一系列其中围绕C1'-C2'键的旋转受阻的大麻素。合成中的关键步骤包括将取代的间苯二酚的铜酸盐加成到(+)-阿朴维本酮上、TMSOTf介导的二氢吡喃环的形成以及β-11-羟甲基的立体定向引入。所有测试的类似物对受体均显示出纳摩尔亲和力，顺式庚-1-烯侧链对CB1具有最高亲和力（Ki = 0.89 nM），并且在CB1和CB2亲和力之间显示出最大差异。母体正庚基-β-11-羟基六氢大麻酚与CB1结合的效力最低（Ki = 8.9 nM），并且在CB1和CB2之间具有最低的选择性。
