CONFORMATIONAL EFFECTS ON RETINOID RECEPTOR SELECTIVITY .2. EFFECTS OF RETINOID BRIDGING GROUP ON RETINOID-X-RECEPTOR ACTIVITY AND SELECTIVITY
CONFORMATIONAL EFFECTS ON RETINOID RECEPTOR SELECTIVITY .2. EFFECTS OF RETINOID BRIDGING GROUP ON RETINOID-X-RECEPTOR ACTIVITY AND SELECTIVITY
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DOI：
10.1021/jm00017a021
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发表时间：
1995-08-18
影响因子：
7.3
通讯作者：
PFAHL, M
中科院分区：
文献类型：
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作者：
DAWSON, MI;JONG, L;PFAHL, M
天然类维生素A 9-顺式-视黄酸是视黄酸受体（RAR）和类维生素A X受体（RXR）两者的活化配体，所述受体是通过特异性反应元件活化基因转录的类维生素A/甲状腺激素/类固醇激素核受体蛋白家族的成员。通过评价21种构象限制性类维生素A在存在三种RAR亚型之一或RXR α的情况下激活TREpal视黄酸受体反应元件进行基因转录的能力，建立了赋予RXR选择性所需的药效基团。与对RAR具有选择性的类维生素A相比，这些RXR选择性类维生素A在连接类维生素A骨架的疏水末端和羧酸末端的桥中少了一个原子。因此，一碳桥取代S-顺式-视黄酸的19-甲基和SE-双键，并通过包含在异亚丙基、二氧戊环或环丙烷环中而进一步官能化，以获得最佳的RXR α活性和选择性。此外，g-顺式-视黄酸的β-亚香叶基和20-甲基-（11 E，13 E）-二烯酸基团分别被5，6，7，8-四氢-5，5，8，8-四甲基-2-萘基环和4-羧基苯基环取代，以获得最佳活化和选择性。RXR α;当4-羧基苯基被2-羧基-5-噻吩基或S-顺式-视黄酸甲基异戊烯酸末端取代时，选择性降低。
The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessary to confer RXR selectivity were established by evaluating the ability of 21 conformationally restricted retinoids to activate, the TREpal retinoic acid receptor response element for gene transcription in the presence of one of the three RAR subtypes or RXR alpha. In contrast to those retinoids selective for the RARs, these RXR-selective retinoids have one less atom in the bridge linking the hydrophobic and carboxylic acid termini of the retinoid skeleton. Therefore, a one-carbon bridge replaces the 19-methyl group and SE-double bond of S-cis-retinoic acid and is further functionalized by inclusion in an isopropylidene group, a dioxolane ring, or a cyclopropane ring for optimal RXR alpha activity and selectivity. In addition, the beta-geranylidene and 20-methyl-(11E,13E)-dienoic acid groups of g-cis-retinoic acid are replaced by a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 naphthalenyl ring and a 4-carboxylphenyl ring, respectively, for optimal activation and selectivity. RXR alpha; selectivity is reduced on replacement of the 4-carboxylphenyl group by a 2-carboxyl-5-thienyl group or the S-cis-retinoic acid methylpentadienoic acid terminus.