alpha-Methylated analogues of triiodothyroalkanoic acids: synthesis and biological activity.

Three novel thyroid hormone analogues: alpha-methyl-3,5,3'-triiodothyroacetic acid, alpha-methyl-3,5,3'-triiodothyropropionic acid, and alpha-methyl-3,5,3',5'-tetraiodothyropropionic acid were synthesized. The hepatic thyroid receptor affinity of these analogues was compared to that other available thyroid analogues. The ability of these compounds to increase the activity of two hepatic enzymes and to lower blood cholesterol was compared to that of L-triiodothyronine. alpha-Methyl-3,5,3'-triiodothyroacetic acid was shown to have less nuclear binding affinity, less enzyme inducing ability, but more blood cholesterol lowering ability than triiodothyroacetic acid. alpha-Methyl-3,5,3',5'-tetraiodothyropropionic acid showed less nuclear binding affinity and less enzyme-inducing activity than alpha-methyl-3,5,3'-triiodothyropropionic acid.

Effects of methimazole on the 5'-monodeiodinase activities of various tissues.

Iodothyronine 5'-deiodinases were assayed in preparations of liver, cerebral cortex and brown adipose tissue. Rate profiles at various pH values revealed that methimazole activates the liver enzyme (type I) and inhibits the enzyme from brown adipose tissue (type II). Other results show that the type II enzyme may be activated by methimazole when the concentration of endogenous sulfhydryl cofactor or of dithiothreitol in the system is low. Collectively, these results suggest an interplay between the sulfhydryl (-SH) tautomer of methimazole and the sulfhydryl activators of the enzymes.

Inhibition of dopamine beta-hydroxylase by goitrin, a natural antithyroid compound.

RS-Goitrin can be conveniently prepared by a simplification of the Ettlinger procedure. Goitrin is a moderate inhibitor of purified bovine adrenal dopamine beta-hydroxylase. The administration of goitrin leads to a depression of brain norepinephrine and to an elevation of heart and adrenal dopamine.

Mode of death effect on rat liver iodothyronine 5' deiodinase activity: role of adenosine 3',5' monophosphate.

Liver thyronine 5'-deiodinase activity assayed in crude homogenates in the absence of dithiothreitol (DTT) is increased in rats killed by asphyxia when compared to that of animals killed by phenobarbital injection or decapitation. The addition of cyclic adenosine monophosphate leads to a consistent decrease in observed deiodinase activity, suggesting the possible involvement of this nucleotide in the regulation of this enzyme. The addition of DTT eliminates this effect and suggest a dual regulation of the enzyme by cAMP and physiological sulfhydryl compounds.

Synthesis and adrenergic activity of benzimidazole bioisosteres of norepinephrine and isoproterenol.

The concept of bioisosterism between benzimidazole and catechol was applied to the design and synthesis of benzimidazole analogues of norepinephrine, (R,S)-1-[5(6)-benzimidazolyl]-2-aminoethanol (2), and of isoproterenol, (R,S)-1-[5(6)-benzimidazolyl]-2-isopropylaminoethanol (4). Compound 2 was shown to be a partial bioisostere of norepinephrine, with direct agonist activity at the alpha-adrenergic receptor. The ED50 for 2 in contracting the guinea pig isolated aortic strip was determined to be 8.0 x 10(-6) M. Compound 4 was shown to be a partial bioisostere of isoproterenol, with direct activity as a beta-adrenergic agonist. The ED50 values for positive chronotropic and inotropic effects of 4 on the isolated guinea pig atrial preparation were determined to be 6.2 x 10(-6) and 3.8 x 10(-6) M, respectively. The ED50 for 4 on the isolated guinea pig tracheal preparation was determined to be 1.6 x 10(-6) M. These results indicate that 4 shows greater selectively for the beta-2 adrenergic receptor than does isoproterenol. The chemical stability of benzimidazole, compared with that of catechol, suggests that benzimidazole bioisosteres of catecholamines may be of value as adrenergic drugs.

Carcinogens 3,4-benzpyrene and 3-methylcholanthrene: induction of mitochondrial oxidative enzymes.

Sections of liver from rats injected with 3,4-benzpyrene and 3-methylcholanthrene, when incubated in mediums specific for the histochemical demonstration of mitochondrial oxidative enzymes, show greater activity of several of these enzymes than do sections from control rats. This observation was confirmed by comparison of the staining of mitochondria isolated from the control and from "induced" rats. The fact that an inhibitor of protein synthesis, actinomycin D, effectively diminished the stimulation provided evidence that the stimulation of activity is due to an increase in enzyme synthesis, generally called induction.