Wiley J L, Compton D R, Dai D, Lainton J A, Phillips M, Huffman J W, Martin B R
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia, USA.
J Pharmacol Exp Ther. 1998 Jun;285(3):995-1004.
Early molecular modeling studies with Delta9-tetrahydrocannabinol (Delta9-THC) reported that three discrete regions which interact with brain cannabinoid (CB1) receptors corresponded to the C-9 position of the cyclohexene ring, the phenolic hydroxyl and the carbon side chain at the C3 position. Although the location of these attachment points for aminoalkylindoles is less clear, the naphthalene ring, the carbonyl group and the morpholinoethyl group have been suggested as probable sites. In this study, a series of indole- and pyrrole-derived cannabinoids was developed, in which the morpholinoethyl group was replaced with another cyclic structure or with a carbon chain that more directly corresponded to the side chain of Delta9-THC and were tested for CB1 binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, hypothermia and catalepsy in mice and discriminative stimulus effects in rats. Receptor affinity and potency of these novel cannabinoids were related to the length of the carbon chain. Short side chains resulted in inactive compounds, whereas chains with 4 to 6 carbons produced optimal in vitro and in vivo activity. Pyrrole-derived cannabinoids were consistently less potent than were the corresponding indole derivatives and showed pronounced separation of activity, in that potencies for hypomobility and antinociception were severalfold higher than potencies for hypothermia and ring immobility. These results suggest that, whereas the site of the morpholinoethyl group in these cannabinoids seems crucial for attachment to CB1 receptors, the exact structural constraints on this part of the molecule are not as strict as previously thought.
早期对 Δ9-四氢大麻酚（Δ9-THC）的分子建模研究报告称，与脑大麻素（CB1）受体相互作用的三个离散区域分别对应环己烯环的 C-9 位、酚羟基以及 C3 位的碳侧链。尽管氨基烷基吲哚这些附着点的位置尚不太明确，但有人提出萘环、羰基和吗啉代乙基可能是附着位点。在本研究中，开发了一系列吲哚和吡咯衍生的大麻素，其中用另一种环状结构或更直接对应于 Δ9-THC 侧链的碳链取代了吗啉代乙基，并对其进行了 CB1 结合亲和力测试以及一系列体内测试，包括小鼠的运动减少、抗伤害感受、体温过低和僵住反应，以及大鼠的辨别刺激效应。这些新型大麻素的受体亲和力和效力与碳链长度有关。短侧链导致化合物无活性，而含有 4 至 6 个碳的链产生了最佳的体外和体内活性。吡咯衍生的大麻素的效力始终低于相应的吲哚衍生物，并且表现出明显的活性差异，即运动减少和抗伤害感受的效力比体温过低和环僵住的效力高几倍。这些结果表明，虽然这些大麻素中吗啉代乙基的位点似乎对与 CB1 受体的附着至关重要，但分子这一部分的确切结构限制并不像先前认为的那么严格。
