Nichols David E, Sassano M Flori, Halberstadt Adam L, Klein Landon M, Brandt Simon D, Elliott Simon P, Fiedler Wolfgang J
†Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
∥School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, U.K.
ACS Chem Neurosci. 2015 Jul 15;6(7):1165-75. doi: 10.1021/cn500292d. Epub 2015 Jan 21.
A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had the highest affinity at the 5-HT2 family receptors. Substitution at the para position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or the meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca(2+) mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head twitch and that there was a significant correlation between this behavior and functional potency at the rat 5-HT2A receptor.
制备并研究了一系列N-苄基化-5-甲氧基色胺类似物，特别关注苄基间位的取代基。还包括一系列平行的2,5-二甲氧基-4-碘苯乙胺（2C-I）的N-苄基化类似物，用于比较两种主要模板（即色胺和苯乙胺）。在5-羟色胺受体上进行的广泛亲和力筛选表明，大多数化合物在5-HT2家族受体上具有最高亲和力。苄基对位的取代导致亲和力降低，而邻位或间位的取代则增强亲和力。一般来说，引入大的亲脂性基团可提高亲和力，而功能活性往往呈现相反的趋势。利用细胞内Ca(2+)动员对化合物的功能活性进行测试。在人5-HT2A、5-HT2B和5-HT2C受体以及大鼠5-HT2A和5-HT2C受体上测量功能。亲和力与功能之间没有普遍的相关性。几种色胺同系物在功能上非常有效（EC50值为7.6至63 nM），但大多数是部分激动剂。在小鼠头部抽搐试验中的测试表明，许多化合物会诱发头部抽搐，并且这种行为与大鼠5-HT2A受体的功能效力之间存在显著相关性。
