Synthesis and serotonin binding site studies of some conformationally restricted indolylethylamine analogues based on 2-amino-3-(3'-indolyl)bicyclo[2.2.2]octane.
Synthesis and serotonin binding site studies of some conformationally restricted indolylethylamine analogues based on 2-amino-3-(3'-indolyl)bicyclo[2.2.2]octane.
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基于2-氨基-3-(3-吲哚基)双环[2.2.2]辛烷的一些构象限制的吲哚基乙胺类似物的合成和血清素结合位点研究。
DOI：
10.1021/jm00163a062
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发表时间：
1990
影响因子：
7.3
通讯作者：
Debler,EA
中科院分区：
文献类型：
--
作者：
Schlecht,MF;Tsarouhtsis,D;Lipovac,MN;Debler,EA
环己烯酮和吲哚基烯胺之间的双环成环反应产生反式-3-（环氨基）-2-（3 '-吲哚基）双环[2.2. 2]辛-5-酮，并且这些加合物是吲哚基乙胺（色胺）的构象受限类似物，其对5-羟色胺5 HT 2和5 HT 1受体表现出结构依赖性亲和力。通过Bamford-Stevens反应从酮制备的特定氘代烯烃的NMR谱，对所获得的异构体内加合物和外加合物的立体化学进行了归属。分子力学计算表明，氨基和吲哚基团的构象灵活性是通过与双环单元的桥的货车德瓦尔斯相互作用来限制的。这些化合物抑制[3 H]酮色林与小鼠大脑皮层膜中5 HT 2位点的结合，以及[3 H]-8-羟基-2-（二正丙基氨基）四氢萘（[3 H]-8-OH-DPAT）与小鼠海马膜中5 HT 1a位点的结合。内型化合物是最有效的，分子力学计算表明，这些异构体具有较小体积的二环桥接近胺基和更多的构象自由度的Ca-Cg-N+-H二面角（r3）。在5 HT 2测定中，内-反式-3-（N-哌啶基）-2-（3吲哚基）二环[2.2. 2]辛-5-酮（10a）是最有效的，而内-反式-3-（N-吡咯烷基）-2-（3 ′-吲哚基）双环[2.2. 2]辛-5-烯（12 α）在5 HT 1a测定中是最有效的。苯基取代的加合物在这两种测定中显示出最小的亲和力。这些数据为深入了解5-HT 1a和5-HT 2受体位点的结构差异提供了线索，构象受限的芳基乙胺类化合物可作为研究这些重要生理活性物质结合位点结构的有效工具。目前，许多努力针对开发以高特异性结合血清素结合位点亚型的化合物，以便更好地评估这些众多受体的结构和功能特征。5-羟色胺受体仍然知之甚少，关于在特定5-羟色胺结合位点亚型结合的要求的更具体的信息应有助于设计更特异性的激动剂和拮抗剂。活性类似物也是新的选择性药物的候选者。我们正在研究的构效关系，支配的亲和力构象限制类似物的5-羟色胺结合位点，我们在这里报告的合成和表征的吲哚乙胺（色胺）类似物9、10、12和13和苯乙胺类似物11，并研究了它们抑制氚化酮色林与小鼠脑皮层膜中5 HT 2位点结合和氚化8-羟基-2-羟色胺与小鼠脑皮层膜中5 HT 2位点结合的活性。（二正丙基氨基）四氢化萘（8-OH-DPAT）与小鼠海马膜中的5 HT 1a位点的结合。3我们已经开发了吲哚乙胺类似物的简易制备方法，其中吲哚和胺部分以邻位反式方式连接到乙醇上。
The bicycloannulation reaction between cyclohexenone and indolyl enamines yields trans-3-(cyclic amino)-2-(3'-indolyl) bicyclo [2.2. 2] octan-5-ones, and these adducts are conformationally restricted analogues of indolylethylamine (tryptamine) which exhibit structure-dependent affinity for the serotonin 5HT2 and 5HTlareceptors. The stere-ochemistry of the isomeric endo and exo adducts obtained is assigned from the NMR spectra of the specifically deuterated alkenes prepared from the ketones by the Bamford-Stevens reaction. Molecular mechanics calculations indicate that the conformational flexibility of the aminoand indolyl groups is restricted through van der Waals interactions with the bridges of the bicyclic unit. These compounds inhibit the binding of [3H] ketanserin to 5HT2 sites in mouse cerebrocortical membranes, and the binding of [3H]-8-hydroxy-2-(di-n-propylamino) tetralin ([3H]-8-OH-DPAT) to 5HTla sites in mouse hippocampal membranes. The endo compounds are the most potent, and molecular mechanics calculations indicate that these isomers have a less bulky bicyclo bridge proximate to the amine group and more conformational freedom about the Ca-Cg-N+-H dihedral angle (r3). In the 5HT2 assay, endo-trans-3-(iV-piperidinyl)-2-(3'-indolyl) bicyclo [2.2. 2] octan-5-one (10a) is the mostpotent, and endo-trans-3-(N-pyrrolidinyl)-2-(3'-indolyl) bicyclo [2.2. 2] oct-5-ene (12a) is the most potent in the 5HTla assay. A phenyl-substituted adduct shows the least affinity in these two assays. These data provideinsight into the structural differences between the 5HTla and 5HT2 receptor sites.Conformationally restricted synthetic analogues of bioactive arylethylamines can be used as effective tools for probing the structure of the binding sites for these phys-iologically important substances. Much effort is currently directed to the development of compounds that bind, with high specificity, to serotonin binding site subtypes in order better to evaluate structural and functional features of these numerous receptors. 1, 2 The serotonin receptors are still very poorly understood, and more specific information on the requirements for binding at particular serotonin binding site subtypes should facilitate thedesign of more specific agonists and antagonists. Active analogues are also candidates for new selective drugs. We are investigating the structure-activity relationships that govern the affinity of conformationally restricted analogues for serotonin binding sites, and we report here the synthesis and characterization of the indolylethylamine (tryptamine) analogues 9, 10, 12, and 13 and the phenylethylamine analogue 11, and studies on their activity at inhibiting the binding of tritiated ketanserin to 5HT2 sites in mouse cerebrocortical membranes and of tritiated 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) to 5HTla sites in mouse hippocampal membranes. 3 We have developed a facile preparation of indolylethylamine analogues in which the indole and amine moieties are attached in a vicinal trans fashion to an ethano
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缓激肽刺激猪主动脉内皮细胞中肌醇多磷酸的产生。
DOI：
--
发表时间：
1986
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Lambert,TL;Kent,RS;Whorton,AR
通讯作者：
Whorton,AR
细胞质钙浓度的升高刺激鸡心脏细胞中磷脂酰肌醇二磷酸的水解：钠通道激活剂的作用。
影响因子：
3.6
作者：
McDonough,PM;Goldstein,D;Brown,JH
通讯作者：
Brown,JH
受体和磷酸肌醇产生的第二信使。
影响因子：
16.6
作者：
Hokin,LE
通讯作者：
Hokin,LE
锂对体内磷酸肌醇代谢的影响。
DOI：
--
发表时间：
1986
期刊：
Federation proceedings
影响因子：
--
作者：
Sherman,WR;Gish,BG;Honchar,MP;Munsell,LY
通讯作者：
Munsell,LY
动物组织中多种形式的不同相对分子质量的磷酸肌醇特异性磷脂酶 C。
DOI：
10.1042/bj2210813
发表时间：
1984
期刊：
The Biochemical journal
影响因子：
--
作者：
Low,MG;Carroll,RC;Weglicki,WB
通讯作者：
Weglicki,WB