Structure-Activity Relationships of Retinoids in Developmental Toxicology

The teratogenic potency of retinoid analogs was determined in Syrian hamsters and compared to the teratogenic potency of all-trans-retinoic acid (all-trans.-RA, ED50 = 10.5 mg/kg). A total of 15 analogs having variations in the cyclohexene ring were evaluated following various amounts of single oral doses on day 8 of gestation. Retinoids containing a five- or six-membered ring were as teratogenic as all-tmru.-RA, provided they had sufficient lipophilic substituents on the ring. The same pattern emerged for retinoids that had six-membered aromatic ring substitution for the natural cyclohexene ring of vitamin A. Incorporation of a supplementary aromatic ring in the side-chain adjacent to a gem-dimethyl-hexene ring resulted in an increase in teratogenicity by IS-fold compared to all-trans.-RA. Major modifications of the cyclohexene ring can be made without altering teratogenic activity. The ring need not be six-membered and can have decreased lipophilicity through the incorporation of polar groups compared to all-trans.-RA, but must have sufficient lipophilic substituents to provide the necessary mass for interaction with the retinoid receptor. Incorporation of a supplementary aromatic ring adjacent to a gem-dimethyl-hexene ring facilitated π-electron delocalization and restricts side-chain flexibility , thereby increasing teratogenic potency. The pharmacokinetic disposition of 8 retinoids was investigated. Pregnant hamsters were dosed orally with all-trans-RA, 13-cis-retinoic acid, all-trans.-4- oxoretinoic acid, 9-cis-retinal, all-trans.-retinyl acetate, N-ethyl-all-trans- retinamide, N-ethyl-13-cis-retinamide, and arotinoid. The bioavailability of the retinamides was one-tenth that of the free acid retinoids. The plasma elimination half-life for all-trans-RA was 0.5 h. For 13-cis-retinoic acid and all-trans-4-oxoretinoic acid the elimination half-lives were 4.4 and 5.7 h, respectively. The binding affinity of various retinoids to cellular retinoic acid-binding protein (cRABP) was determined in day-12 hamster fetuses. Fetal supernatants from the 105,000x g fraction were incubated with high specific-activity [3H]-all-trans-RA in the presence of various concentration of unlabeled retinoids with subsequent isolation of cRABP by size-exclusion HPLC. Teratogenic retinoids, or acidic metabolites of teratogenic retinoids bound to cRABP whereas nonteratogenic retinoids failed to bind