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Molecular Pharmacology

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Research ArticleArticle

Bone-Resorbing Activity of Analogues of 25-Hydroxycholecalciferol and 1,25-Dihydroxycholecalciferol: Effects of Side Chain Modification and Stereoisomerization on Responses of Fetal Rat Bones in Vitro

PAULA H. STERN, THALIA MAVREAS, CLARENCE L. TRUMMEL, HEINRICH K. SCHNOES and HECTOR F. DELUCA
Molecular Pharmacology November 1976, 12 (6) 879-886;
PAULA H. STERN
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611
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THALIA MAVREAS
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CLARENCE L. TRUMMEL
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HEINRICH K. SCHNOES
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HECTOR F. DELUCA
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Abstract

Organ cultures of fetal rat bone were used to test the effects of molecular modification on the bone-resorbing activity of the vitamin D3 metabolites 25-OH-D3 and 1,25-(OH)2D3. Addition of 26-hydroxyl group to the 25-OH-D3 side chain reduced the activity more than 10-fold. Shortening the 25-OH-D3 side chain by 1 carbon atom reduced the activity by at least two orders of magnitude. Removal of the 26- and 27-methyl groups diminished the bone-resorbing activity still further. 1,25-(OH)2D3 was likewise more active than the vitamin D3 derivatives with which it was compared. The 3α-hydroxy epimer of 1,25-(OH)2D3 [1,25-(OH)2D3 (3α)] was more than three orders of magnitude less active than 1,25-(OH)2D3. 1,24(R),25-(OH)3D3 was approximately 1/10 as active as 1,25-(OH)2D3. When the 24-hydroxyl was in the S configuration, the trihydroxy derivative was even less effective. 1,25-(OH)2D3 was approximately equiactive with 1,25-(OH)2D2. The results illustrate the importance of precise structural characteristics at a number of sites on the molecule for optimal bone-resorbing activity. The data also show that in terms of direct effects on bone, no known naturally occurring vitamin D3 metabolite or synthetic congener surpasses 1,25-(OH)2D3 in activity. A striking correlation exists between the structure-activity relationships shown here and published studies on the binding of vitamin D analogues to subcellular "receptors." Good correlations also can be demonstrated between effects of the 1-hydroxylated derivatives on bone resorption in vivo and in vitro. Greater inconsistencies between results in vitro and in vivo are found with compounds lacking a 1-hydroxyl group.

  • Copyright © 1976 by Academic Press, Inc.

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Molecular Pharmacology
Vol. 12, Issue 6
1 Nov 1976
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Research ArticleArticle

Bone-Resorbing Activity of Analogues of 25-Hydroxycholecalciferol and 1,25-Dihydroxycholecalciferol: Effects of Side Chain Modification and Stereoisomerization on Responses of Fetal Rat Bones in Vitro

PAULA H. STERN, THALIA MAVREAS, CLARENCE L. TRUMMEL, HEINRICH K. SCHNOES and HECTOR F. DELUCA
Molecular Pharmacology November 1, 1976, 12 (6) 879-886;

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Research ArticleArticle

Bone-Resorbing Activity of Analogues of 25-Hydroxycholecalciferol and 1,25-Dihydroxycholecalciferol: Effects of Side Chain Modification and Stereoisomerization on Responses of Fetal Rat Bones in Vitro

PAULA H. STERN, THALIA MAVREAS, CLARENCE L. TRUMMEL, HEINRICH K. SCHNOES and HECTOR F. DELUCA
Molecular Pharmacology November 1, 1976, 12 (6) 879-886;
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