3-indolyl-1-naphthylmethanes:: New cannabimimetic Indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor
3-indolyl-1-naphthylmethanes:: New cannabimimetic Indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor
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DOI：
10.1016/s0968-0896(02)00451-0
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发表时间：
2003-02-20
影响因子：
3.5
通讯作者：
Martin, BR
中科院分区：
文献类型：
--
作者：
Huffman, JW;Mabon, R;Martin, BR
合成了一系列1-戊基-1H-吲哚-3-基-(1-萘基)甲烷(9-11)和2-methyl-1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes(12-14)，研究了模拟大麻的3-(1-萘甲酰基)吲哚与CB I受体通过与羰基氢键相互作用的假说。吲哚类化合物9-11具有显著的(K-I 17-23 nm)受体亲和力，略低于相应的萘基吲哚类化合物(5，15，16)。2-甲基-1-吲哚12-14与CB1受体的亲和力很小，而2-甲基-3-(1-萘酰基)吲哚17-19的亲和力与5，15，16的亲和力相当。合成了一种拟大麻的吲哚烃(26)，其K-i=26+/-4 nm。对萘甲酰吲哚16、其2-甲基同系物(19)和吲哚-1-萘基甲烷11和14的分子模拟和受体对接研究，结合这些拟大麻吲哚的受体亲和力，强烈表明这些大麻受体配体主要通过CB1受体跨膜螺旋3-4-5-6区域的芳香堆积作用结合。(C)2002爱思唯尔科学有限公司。保留所有权利。
A series of 1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (9 11) and 2-methyl-1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (12-14) have been synthesized to investigate the hypothesis that cannabimimetic 3-(1-naphthoyl)indoles interact with the CB I receptor by hydrogen bonding to the carbonyl group. Indoles 9-11 have significant (K-i 17-23 nM) receptor affinity, somewhat less than that of the corresponding naphthoylindoles (5, 15, 16). 2-Methyl-1-indoles 12-14 have little affinity for the CB1 receptor, in contrast to 2-methyl-3-(1-naphthoyl)indoles 17-19, which have affinities comparable to those of 5, 15, 16. A cannabimimetic indene hydrocarbon (26) was synthesized and found to have K-i = 26 +/- 4 nM. Molecular modeling and receptor docking studies of naphthoylindole 16, its 2-methyl congener (19) and indolyl-1-naphthylmethanes 11 and 14, combined with the receptor affinities of these cannabimimetic indoles, strongly suggest that these cannabinoid receptor ligands bind primarily by aromatic stacking interactions in the transmembrane helix 3-4-5-6 region of the CB1 receptor. (C) 2002 Elsevier Science Ltd. All rights reserved.