Mineralocorticoid activity of 21-deoxyaldosterone derivatives: Structure-function studies

doi:10.1016/0022-4731(81)90213-2

Journal of Steroid Biochemistry

Volume 14, Issue 10, October 1981, Pages 1041-1044

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Abstract

The synthesis of 21-deoxyaldosterone was undertaken to determine whether it has a possible role as a mineralocorticoid antagonist in human metabolism. It was found that the synthetic 11,18-hemiacetal form of 21-deoxyaldosterone could be converted to a 20-methyl ether when exposed to silica gel and methanol during high performance liquid chromatography. The preparation of a 11,18-acetal-18,20 hemiketal isomer and other derivatives of 21-deoxyaldosterone are described and proton n.m.r. data presented.

The 20-methyl ether of 21-deoxyaldosterone has one third the affinity of aldosterone for rat kidney mineralocorticoid receptors; on bioassay, however, it shows only ~ 1% the agonist activity of aldosterone, and no antagonist activity. 21-Deoxyaldosterone 18-acetate, the 18-methyl ether and the free 20-hemiketal isomer, in contrast, have low affinity for mineralocorticoid receptors (~2% that of aldosterone) 17-iso-21-deoxyaldosterone has negligible affinity. Before possible (patho)-physiological roles can be assigned to any naturally occurring 21-deoxy metabolite of aldosterone, therefore, it would appear necessary to establish both its isomeric state and in vivo stability

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HPLC isolation and GC-MS characterization of a compound strongly cross reacting with tetrahydroaldosterone antiserum
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Urines from patients with hypertension and elevated aldosterone levels, i.e. primary aldosteronism due to adrenal adenoma or hyperplasia or carcinoma were extracted, paper chromatographed and thereafter chromatographed repeatedly with normal phase and repeatedly with reversed phase HPLC systems in an attempt to find new metabolites of aldosterone. Specific 3α-hydroxy-5β-tetrahydroaldosterone antiserum was used in a radioimmunoassay system to detect possible aldosterone metabolites in the HPLC fractions after each isolation step. The immunoactive HPLC fractions were derivatized and analysed by GC-MS. A relatively nonpolar compound, 11β:18(S),18:20α-diepoxy-5β-pregnan-3α-ol, was isolated and identified in this manner. This material was originally described by Kelly et al., in 1962 [23] after loading human subjects with huge amounts (25–160 mg) of exogenous aldosterone. This material has not yet been described from endogenously produced aldosterone. Very small amounts, if any, were similarly isolated from the urine of a control subject. Therefore, this compound could prove to be a new marker for hypertension due to hyper-production of aldosterone.
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Mineralocorticoid and renal receptor binding activity of 21-deoxyaldosterone
1990, Endocrinology
21-Deoxyaldosterone excretion in patients with primary aldosteronism and 21-hydroxylase deficiency
1987, Journal of Clinical Endocrinology and Metabolism

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Mineralocorticoid activity of 21-deoxyaldosterone derivatives: Structure-function studies

Abstract

J. steroid Biochem

J. steroid Biochem.

The roles of plasma binding and receptor specificity in the mineralocorticoid action of aldosterone

Endocrinology

Actions of hormones on the kidney

Ann. Rev. Physiol.

Biliary excretion and bacterial metabolism of mineralocorticoids

Isolation and characterization of aldosterone metabolites from human urine; two metabolites bearing a bicyclic acetal structure

Biochemistry

Substitution at unactivated carbon. The synthesis of 18-and 19-substituted derivatives of 11β-hydroxy-progesterone

J. org. Chem.