Garratt P J, Jones R, Tocher D A, Sugden D
Department of Chemistry, University College London, U.K.
J Med Chem. 1995 Mar 31;38(7):1132-9. doi: 10.1021/jm00007a010.
Three series of 2-phenyltryptamides were prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor in chicken brain and in Xenopus laevis melanophore cells. The 5-methoxy-2-phenyltryptamides (6a-j) have high binding affinities for the chicken brain receptor, in some cases (6a-d) greater than that for melatonin, confirming and extending the work of Spadoni et al., and act as agonists in the Xenopus melanophore assay. Analogues lacking the 5-methoxyl group (2a-n) had a considerably lower affinity for the chicken brain receptor. In the Xenopus melanophore assay the compounds acylated on nitrogen by an alkyl group (2a-d) were agonists whereas the compounds acylated on nitrogen by an alicyclic group (2f-i) were antagonists. Introducing a methyl group at N1 (7) led to an increase in binding affinity in the chicken brain assay, whereas introducing an ethyl group (13) led to a decrease in binding affinity. A methyl substituent at the beta-position of the 3-amidoethane side chain (8, 11) also led to an increase in the binding affinity. The only analogue acylated on nitrogen with an alkyl group (acetyl) which showed antagonist activity was 9, which has a beta-methoxymethyl side chain. In the absence of the 5-methoxyl group the methoxymethyl function may cause the molecule to bind in a different configuration so that it is no longer able to activate the receptor. All of these observations are in agreement with a model of melatonin at the receptor site in which the 3-amidoethane side chain is in a conformation close to the 5-methoxyl group.
制备了三组2-苯基色胺作为褪黑素类似物，以研究鸡脑和非洲爪蟾黑素细胞中褪黑素受体结合位点的性质。5-甲氧基-2-苯基色胺（6a-j）对鸡脑受体具有高结合亲和力，在某些情况下（6a-d）高于褪黑素，证实并扩展了Spadoni等人的工作，并且在非洲爪蟾黑素细胞试验中作为激动剂起作用。缺乏5-甲氧基的类似物（2a-n）对鸡脑受体的亲和力相当低。在非洲爪蟾黑素细胞试验中，氮上被烷基酰化的化合物（2a-d）是激动剂，而氮上被脂环族基团酰化的化合物（2f-i）是拮抗剂。在N1位引入甲基（7）导致鸡脑试验中结合亲和力增加，而引入乙基（13）导致结合亲和力降低。3-氨基乙烷侧链β位的甲基取代基（8,11）也导致结合亲和力增加。唯一氮上被烷基（乙酰基）酰化且显示拮抗剂活性的类似物是9，其具有β-甲氧基甲基侧链。在没有5-甲氧基的情况下，甲氧基甲基官能团可能导致分子以不同构型结合，从而使其不再能够激活受体。所有这些观察结果都与褪黑素在受体位点的模型一致，其中3-氨基乙烷侧链处于接近5-甲氧基的构象。
