CONFORMATIONAL EFFECTS ON RETINOID RECEPTOR SELECTIVITY .2. EFFECTS OF RETINOID BRIDGING GROUP ON RETINOID-X-RECEPTOR ACTIVITY AND SELECTIVITY

The natural retinoid 9-cis-retinoic acid is an activating ligand for b oth the retinoic acid receptors (RARs) and the retinoid X receptors (R XRs), which are members of the retinoid/thyroid hormone/steroid hormon e family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessa ry to confer RXR selectivity were established by evaluating the abilit y 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 carboxyl ic acid termini of the retinoid skeleton. Therefore, a one-carbon brid ge replaces the 19-methyl group and SE-double bond of S-cis-retinoic a cid and is further functionalized by inclusion in an isopropylidene gr oup, a dioxolane ring, or a cyclopropane ring for optimal RXR alpha ac tivity and selectivity. In addition, the beta-geranylidene and 20-meth yl-(11E,13E)-dienoic acid groups of g-cis-retinoic acid are replaced b y a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 naphthalenyl ring and a 4 -carboxylphenyl ring, respectively, for optimal activation and selecti vity. RXR alpha; selectivity is reduced on replacement of the 4-carbox ylphenyl group by a 2-carboxyl-5-thienyl group or the S-cis-retinoic a cid methylpentadienoic acid terminus.