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9-氨甲基-9,10-二氢蒽（AMDA）类似物作为 5-HT2A 和 H1 受体结合部位空间位阻耐受性的结构探针。

9-Aminomethyl-9,10-dihydroanthracene (AMDA) analogs as structural probes for steric tolerance in 5-HT2A and H1 receptor binding sites.

机构信息

Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.

出版信息

Bioorg Med Chem Lett. 2010 Feb 1;20(3):935-8. doi: 10.1016/j.bmcl.2009.12.064. Epub 2009 Dec 23.

DOI:10.1016/j.bmcl.2009.12.064
PMID:20045641
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3252747/
Abstract

Synthesis, radioligand binding and molecular modeling studies of several 9-aminomethyl-9,10-dihydroanthracene (AMDA) analogs were carried out to determine the extent of the steric tolerance associated with expansion of the tricyclic ring system and amine substitution at 5-HT(2A) and H(1) receptors. A mixture of (7,12-dihydrotetraphene-12-yl)methanamine and (6,11-dihydrotetracene-11-yl)methanamine in a 75-25% ratio was found to have an apparent K(i) of 10nM at the 5-HT(2A) receptor. A substantial binding affinity for (7,12-dihydrotetraphene-3-methoxy-12-yl)methanamine at the 5-HT(2A) receptor (K(i)=21 nM) was also observed. Interestingly, this compound was found to have 100-fold selectivity for 5-HT(2A) over the H(1) receptor (K(i)=2500 nM). N-Phenylalkyl-AMDA derivatives, in which the length of the alkyl chain varied from methylene to n-butylene, were found to have only weak affinity for both 5-HT(2A) and H(1) receptors (K(i)=223 to 964 nM). Our results show that large rigid annulated AMDA analogs can be sterically accommodated within the proposed 5-HT(2A) binding site.

摘要

合成、放射性配体结合和分子建模研究了几种 9-氨甲基-9,10-二氢蒽（AMDA）类似物，以确定三环系统扩展和 5-HT（2A）和 H（1）受体上的胺取代所带来的空间位阻容忍度。发现（7,12-二氢四苯-12-基）甲胺和（6,11-二氢四苯-11-基）甲胺的混合物以 75-25%的比例在 5-HT（2A）受体上具有 10 nM 的表观 K(i)。还观察到（7,12-二氢四苯-3-甲氧基-12-基）甲胺在 5-HT（2A）受体上具有相当大的结合亲和力（K(i)=21 nM）。有趣的是，发现该化合物对 5-HT（2A）受体具有 100 倍的选择性，对 H（1）受体的选择性（K(i)=2500 nM）。N-芳基烷基-AMDA 衍生物中，烷基链的长度从亚甲基变化到正丁烯，发现对 5-HT（2A）和 H（1）受体的亲和力都很弱（K(i)=223 至 964 nM）。我们的结果表明，大的刚性稠合 AMDA 类似物可以在拟议的 5-HT（2A）结合位点内容纳。

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1
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2
The expanded biology of serotonin.
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3
Sequence-derived three-dimensional pharmacophore models for G-protein-coupled receptors and their application in virtual screening.
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4
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5
Potential modes of interaction of 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives with the 5-HT2A receptor: a ligand structure-affinity relationship, receptor mutagenesis and receptor modeling investigation.
J Med Chem. 2008 Nov 13;51(21):6808-28. doi: 10.1021/jm800771x. Epub 2008 Oct 11.
6
Methoxy-substituted 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives exhibit differential binding affinities at the 5-HT(2A) receptor.
Bioorg Med Chem Lett. 2008 Oct 1;18(19):5268-71. doi: 10.1016/j.bmcl.2008.08.059. Epub 2008 Aug 22.
7
Serotonin receptors.
Chem Rev. 2008 May;108(5):1614-41. doi: 10.1021/cr078224o. Epub 2008 May 14.
8
Two novel series of allocolchicinoids with modified seven membered B-rings: design, synthesis, inhibition of tubulin assembly and cytotoxicity.
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9
Modeller: generation and refinement of homology-based protein structure models.
Methods Enzymol. 2003;374:461-91. doi: 10.1016/S0076-6879(03)74020-8.
10
Multiple sequence alignment with the Clustal series of programs.
Nucleic Acids Res. 2003 Jul 1;31(13):3497-500. doi: 10.1093/nar/gkg500.

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