Structure-activity relationships for a novel series of citalopram (1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile) analogues at monoamine transporters.
Structure-activity relationships for a novel series of citalopram (1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile) analogues at monoamine transporters.
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DOI：
10.1021/jm1005034
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发表时间：
2010-08-26
影响因子：
7.3
通讯作者：
Newman AH
中科院分区：
文献类型：
--
作者：
Zhang P;Cyriac G;Kopajtic T;Zhao Y;Javitch JA;Katz JL;Newman AH
(±)-西妥普兰(1，1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1，3-dihydroisobenzofuran-5-carbonitrile)，及其正构体，S(+)-1)是临床上用于治疗焦虑和抑郁的选择性5-羟色胺再摄取抑制剂(SSRIs)。为了进一步探讨5-羟色胺转运体(SERT)的构效关系，设计、合成和评价了一系列(±)-4-和5-取代西酞普兰类似物与SERT、多巴胺转运体(DAT)和去甲肾上腺素转运体(NET)的结合。许多类似物在Net和DAT上都表现出高的SERT结合亲和力(Ki=1-40 nM)和选择性。合成了精选的对映体类似物对，两者都保持了S-和R-1的对映体选择性，其中S和R在SERT。此外，1和5的对映体对在同源细菌亮氨酸转运体(Leut)上进行了结合测试，其中低亲和力和没有对映体选择性表明这些化合物在SERT上与Leut有不同的结合部位。这些新的配体将提供分子工具来阐明SERT上的药物-蛋白质相互作用，并将这些与体内的行为行为联系起来。
(±)-Citalopram (1, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile), and its eutomer, escitalopram (S(+)-1) are selective serotonin reuptake inhibitors (SSRIs) that are used clinically to treat anxiety and depression. To further explore structure-activity relationships at the serotonin transporter (SERT), a series of (±)-4- and 5-substituted citalopram analogues were designed, synthesized and evaluated for binding at the SERT, dopamine transporter (DAT) and norepinephrine transporter (NET) in native rodent tissue. Many of these analogues showed high SERT binding affinities (Ki = 1–40 nM) and selectivities over both NET and DAT. Selected enantiomeric pairs of analogues were synthesized and both retained enantioselectivity as with S- and R-1, wherein S > R at the SERT. In addition, the enantiomeric pairs of 1 and 5 were tested for binding at the homologous bacterial Leucine transporter (LeuT), wherein low affinities and the absence of enantioselectivity suggested distinctive binding sites for these compounds at SERT as compared to LeuT. These novel ligands will provide molecular tools to elucidate drug-protein interactions at the SERT and to relate those to behavioral actions, in vivo.
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影响因子：
2.9
作者：
Indarte, Martin;Madura, Jeffry D.;Surratt, Christopher K.
通讯作者：
Surratt, Christopher K.
DOI：
10.1126/science.1166777
发表时间：
2008-12-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Singh SK;Piscitelli CL;Yamashita A;Gouaux E
通讯作者：
Gouaux E
影响因子：
64.8
作者：
Singh, Satinder K.;Yamashita, Atsuko;Gouaux, Eric
通讯作者：
Gouaux, Eric
影响因子：
4.8
作者：
Andersen, Jacob;Taboureau, Olivier;Kristensen, Anders S.
通讯作者：
Kristensen, Anders S.
影响因子：
4.8
作者：
Henry, LK;Field, JR;Blakely, RD
通讯作者：
Blakely, RD