CONFORMATIONALLY DEFINED 6-S-TRANS-RETINOIC ACID ANALOGS .2. SELECTIVE AGONISTS FOR NUCLEAR RECEPTOR-BINDING AND TRANSCRIPTIONAL ACTIVITY

We recently demonstrated in animal models that a new conformationally defined RA isomer (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) was as effective as RA in the prevention of skin papillomas but was less toxic. In order to provide more details concerning this improved actio n, we report here the preparation of a homologous conformationally def ined 6-s-trans-retinoid (1) and investigate its ability to interact wi th proteins and to activate gene expression. Four configurational isom ers of 1 were evaluated in binding assays for cellular retinoic acid b inding protein, CRABP (isolated from chick skin); CRABP-I and CRABP-II (cloned from mouse); nuclear retinoic acid receptors (RARs); and nucl ear retinoid X receptors (RXRs). In each assay the all-E-isomer of thi s retinoid had an activity that was comparable to that of (all-E)-RA. However, the 9Z-isomer was at least 200-fold less active than (all-E)- RA in binding to different RARs, while it was only 6-20 times less act ive than (9Z)-RA in binding to different RXRs. In an in vivo transient transfection assay, the all-E-isomer activated a reporter gene contai ning a retinoic acid response element (RARE) with efficiency similar t o (all-E)-RA when expression vectors for either RAR alpha, RAR beta, R AR gamma alone or RAR alpha together with RXR alpha were cotransfected . In contrast, the 9Z-isomer was much less active than (9Z)-RA. in the same assay systems. However, (9Z)-1 efficiently enhanced the DNA bind ing and transactivational activity of RXR alpha homodimers. Taken toge ther, these studies demonstrate that the all-E- and 9Z-isomers of this retinoid are selective and potent agonists of RAR and RXR binding and activation.