3'-Acetyl-3,5-diiodo-L-thyronine: a novel highly active thyromimetic with low receptor affinity.
The 4'-phenolic hydroxyl group of thyroid hormones plays an important role in receptor binding, and it has been suggested that the interaction of this hydroxyl group with the receptor involves hydrogen bonding via donation of the acidic hydrogen in a trans disposition to the 3'-substituent of the hormones. In order to test this hypothesis we have synthesised, and measured the hepatic receptor affinity and thyromimetic activity of 3'-acetyl-3,5-diiodo-L-thyronine (3'-Ac-T2), a compound in which the formation of such a receptor-phenol hydrogen bond is precluded by the presence of a strong intramolecular hydrogen bond between the 3'-acetyl- and 4'-hydroxyl groups. In confirmation of the hypothesis, 3'-Ac-T2 has a low affinity (0.5% of that of 3,5,3'-triiodo-L-thyronine, T3) for the T3-receptor in isolated rat hepatic nuclei. By contrast the thyromimetic activity (assessed by its ability to induce rat hepatic glycerol-3-phosphate dehydrogenase and increase the qO2 of liver slices) was roughly equal to that of T3. This apparent discrepancy was resolved when it was found that the capacity of 3'-Ac-T2 to occupy hepatic receptors after in vivo administration, was about 100 times greater than predicted from its in vitro affinity. The reason for this difference between in vivo and in vitro nuclear binding is unknown at the present time.
D000818:Animals; D004104:Diiodothyronines; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005993:Glycerolphosphate Dehydrogenase / Q000096:biosynthesis; D006728:Hormones / Q000138:chemical synthesis / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000138:chemical synthesis / Q000378:metabolism; D013970:Thyronines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
D004104:Diiodothyronines; D006728:Hormones; D011956:Receptors, Cell Surface; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D013970:Thyronines; C042998:3'-acetyl-3,5-diiodothyronine; D005993:Glycerolphosphate Dehydrogenase