Structure-toxicity relationships of the tetramethylated tetralin and indane analogs of retinoic acid.
The teratogenicity of retinoids containing either tetramethylated tetralin (Ro 13-6307 or Ro 13-2389) or tetramethylated indane (Ro 13-4306) ring system substitutions was compared to the teratogenic potency of all-trans-retinoic acid. Single oral doses, administered to Syrian Golden hamsters at 10:00 A.M. on day 8 of gestation, induced a syndrome of malformations identical to that induced by treatment with all-trans-retinoic acid. These retinoids failed to induce signs of maternal hypervitaminosis A at doses associated with a significant teratogenic response. The tetramethylated tetralin retinoids and indane retinoid were 18 and 2.4 times as embryotoxic on a molar basis, respectively, as all-trans-retinoic acid. Introduction of a supplementary ring in the side-chain restricted polyene chain flexibility and maintained the hydrophobic plane of the chain. The present results are consistent with previous studies showing that the presence of or biotransformation to a free acid congener was necessary for retinoid teratogenic activity in hamsters and that increasing conformational restriction of acidic retinoids increased teratogenic potency.
Center for Environmental Toxicology, Utah State University, Logan 84322-5600.
W B
WB
Howard
C C
CC
Willhite
R P
RP
Sharma
D000014:Abnormalities, Drug-Induced; D000818:Animals; D006224:Cricetinae; D005260:Female; D007189:Indans / Q000633:toxicity*; D007192:Indenes / Q000633:toxicity*; D008647:Mesocricetus; D009281:Naphthalenes / Q000633:toxicity*; D011247:Pregnancy; D013329:Structure-Activity Relationship; D013577:Syndrome; D013723:Teratogens; D013764:Tetrahydronaphthalenes / Q000633:toxicity*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000633:toxicity*
D007189:Indans; D007192:Indenes; D009281:Naphthalenes; D013723:Teratogens; D013764:Tetrahydronaphthalenes; D014212:Tretinoin