Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.

Article Details

Citation

Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao WR, Pfahl M, Lee MO, Shroot B, Pfahl M

Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.

J Med Chem. 1995 Aug 18;38(17):3368-83.

PubMed ID
7650690 [ View in PubMed
]
Abstract

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 9E-double bond of 9-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 9-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 9-cis-retinoic acid methylpentadienoic acid terminus.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BexaroteneRetinoic acid receptor RXR-alphaEC 50 (nM)42N/AN/ADetails
BexaroteneRetinoic acid receptor RXR-betaEC 50 (nM)112N/AN/ADetails
BexaroteneRetinoic acid receptor RXR-gammaEC 50 (nM)122N/AN/ADetails
TretinoinRetinoic acid receptor alphaEC 50 (nM)23N/AN/ADetails
TretinoinRetinoic acid receptor RXR-alphaEC 50 (nM)54N/AN/ADetails
TretinoinRetinoic acid receptor RXR-alphaEC 50 (nM)530N/AN/ADetails
TretinoinRetinoic acid receptor RXR-alphaEC 50 (nM)6N/AN/ADetails
TretinoinRetinoic acid receptor RXR-betaEC 50 (nM)2.6N/AN/ADetails
TretinoinRetinoic acid receptor RXR-betaEC 50 (nM)4.5N/AN/ADetails
TretinoinRetinoic acid receptor RXR-gammaEC 50 (nM)2N/AN/ADetails
TretinoinRetinoic acid receptor RXR-gammaEC 50 (nM)4.3N/AN/ADetails