6'-SUBSTITUTED NAPHTHALENE-2-CARBOXYLIC ACID ANALOGS, A NEW CLASS OF RETINOIC ACID RECEPTOR SUBTYPE-SPECIFIC LIGANDS

The biological response to retinoic acid (RA) and synthetic derivatives (retinoids) is mediated by three nuclear retinoic acid receptors, RARα, β and γ. To explore the potential of retinoids as receptor subtype selective activators, we employed a transcriptional activation assay. Hybrid receptors that recognize an estrogen response element were used to avoid measuring activities of endogenous retinoic acid receptors. In response to retinoic acid, the three hybrid receptors ER-RARα, ER-RARβ and ER-RARγ exhibited the same induction profile as the corresponding wild type receptors RARα, RARβ, and RARγ. Three different retinoids, analogs of 6′-substituted naphthalene-2-carboxylic acid, elicited strong transcriptional activation of γ receptor while no activation of α receptor was observed. Conversely, two retinobenzoic acid analogs showed a limited α selectivity. We conclude that retinoids with unique profiles of retinoic acid receptor subtype selectivity can be defined and tested for their impact on cellular differentiation and for therapeutical applications. © 1991.