褪黑素受体的映射。6。褪黑素受体激动剂和拮抗剂来自6 h-isoindolo (2, 1 a)吲哚,5,6-dihydroindolo (2, 1 a)异喹啉,和6,7-dihydro-5H-benzo [c] azepino (2, 1 a)吲哚。
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浮士德R, Garratt PJ,琼斯R,叶路,Tsotinis, Panoussopoulou M, Calogeropoulou T,格兰MT,爱丁堡D
褪黑素受体的映射。6。褪黑素受体激动剂和拮抗剂来自6 h-isoindolo (2, 1 a)吲哚,5,6-dihydroindolo (2, 1 a)异喹啉,和6,7-dihydro-5H-benzo [c] azepino (2, 1 a)吲哚。
J医学杂志。2000年3月23日,43 (6):1050 - 61。
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10737738 (在PubMed]
- 文摘
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6 h-isoindolo 1 a[2]吲哚(5、7、10、13),5、6-dihydroindolo 1 a[2]异喹啉(20、21)和6,7-dihydro-5H-benzo [c] azepino 1 a[2]吲哚(30)23日,25日,27日已经准备褪黑激素类似物研究褪黑激素受体的结合位点的性质。类似物的亲和力是确定在一个放射性配体结合试验使用克隆人类太(1)和(2)受体亚型表达在NIH 3 t3细胞。受体激动剂和拮抗剂效力测定使用的颜料聚合反应克隆的非洲爪蟾蜍光滑的载黑素细胞。2-methoxyisoindolo[2,划归]吲哚(7模拟)显示更高的约束力的亲和力比父isoindoles (5 a e),而7 a - c受体激动剂的功能分析,7 d和5 a e拮抗剂。2-ethoxyisoindolo[2,划归]吲哚(10模拟)显示减少绑定亲和力与他们的甲氧基类似物相比,虽然5-chloro导数13显示减少相当大的亲和力、效能比7。10-methoxy-5, 6-dihydroindolo 1 a[2]异喹啉(21 a - c)的结合亲和力高于相应的父indoloisoquinolines (20 a - c)在人类受体亚型,和父化合物拮抗剂而10-methoxy衍生物受体激动剂的功能分析。N-cyclobutanecarbonyl衍生品的父母(20 d)和10-methoxyl (21 d)系列有类似的结合亲和力和拮抗剂具有类似的效能。11-methoxy-6, 7-5H-benzo [c] azepino 1 a[2]吲哚(模拟)25日有约束力的亲和力高于相应的父化合物(23模拟)太(2)受体但在MT(1)网站类似的亲和力;所有的化合物都是对手的功能分析。略微改变11-methoxy 11-ethoxy绑定亲和力下降,这是太(2)受体更明显。 All of the derivatives investigated had either the same or a greater affinity for the human MT(2) receptor compared to the mt(1) receptor (range 1:1-1:132). This suggests that the mt(1) and MT(2) receptor pockets differ in their ability to accommodate alkyl groups in the indole nitrogen region of the melatonin molecule. Two compounds (7c and 25c) were tested in functional assays on recombinant mt(1) and MT(2) melatonin receptors. Compound 7c is a potent agonist with some selectivity (44-fold) for the MT(2) receptor, while 25c is an MT(2)-preferring antagonist. Increasing the carbon chain length between N-1 of indole and the 2-phenyl group from n = 1 through n = 3 leads to a fairly regular decrease in the binding affinity, but, remarkably, when n = 3, it converts the methoxy compounds from melatonin agonists to antagonists. The Xenopus melatonin receptor thus cannot accommodate an N-n-alkyl chain attached to a 2-phenyl substituent with n > 2 in the required orientation to induce or stabilize the active receptor conformation.