Receptor-selective retinoid agonists and teratogenic activity

Retinoid mechanism of action is dependent upon interaction with the retinoid nuclear RAR and RXR subfamilies of receptors. Study of ligands selective for the different receptors or which modify that interaction may provide insight into which receptors play roles in or contribute to retinoid teratogenesis. The retinoids considered here include in the RAR alpha-selective arylcarboxamidobenzoic acid CD 336 (Am580), the RAR beta/gamma-selective naphthalenecarboxylic acid CD 135 and the adamantyl-phenylcarboxamidobenzoic acid CD 394, the RAR-selective tetrahydrotetra-methylanthracenylbenzoic acid (TTAB) SRI 3961, the carboxyphenylretinamide SRI 7167-67, and the RXR-selective diarylisopropylidene SR 11217. CD 135 has a 3-fold higher affinity for RAR beta when compared with RAR gamma, whereas CD 394 has a 3-fold higher affinity for RAR gamma when compared with RAR beta. A separate investigation into potential amelioration of retinoid teratogenesis by concomitant administration of the cyclohexanetrione (Ro 31-0521) was also conducted. When pregnant hamsters were given an oral bolus of CD 336 or CD 135 during the early primitive streak stage of gestation, these retinoids proved 60-100 times more potent teratogens than all-trans-retinoic acid. Intubation of CD 394 resulted in production of terata similar to that seen after an equivalent dose of all-trans-retinoic acid. Administration of SRI 3961 found this compound 8000 times more potent than all-trans-retinoic acid, while SRI 7167-67 failed to show any evidence for developmental toxicity even after exposure to 105 mg/kg. Studies with the RXR-selective SR 11217 found it to be far less potent than all-trans-retinoic acid. These data point to the conclusion that those retinoids which have no affinity for retinoid nuclear receptors also have little potential for induction of developmental toxicity at doses which do not also provoke maternal intoxication. Comparing in vitro transcriptional activation of wild-type human RAR for the supertoxic TTNBP (Ro 13-7410) and TTAB (SRI 3961) with their relative teratogenic potency in hamster found that the more toxic congener also had the lower in vitro EC50 transactivation value (at ratios approximating their differential toxicities measured as administered dose). The RAR beta/gamma-selective CD 135 (TTNN) was not as efficient as TTNBP (Ro 13-7410) or TTAB (SRI 3961) in hRAR transactivation and CD 135 was less toxic than either Ro 13-7410 or SRI 3961. Although the RXR-selective SR 11217 failed to elicit terata after moderate doses, malformations consistent with those induced by high doses of retinoic acid could be produced following a single large bolus of SR 11217. Under the conditions here, simultaneous administration of Ro 31-0521 with all-trans-retinoic acid appeared to reduce the total percentage of abnormal fetuses seen after exposure to retinoic acid alone, but fetal body weights remained depressed and the numbers of dead embryos remained elevated, suggesting only limited influence of the cyclohexanetrione on retinoid developmental toxicity.