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, T. Mavreas, C. L. Trummel

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Organ cultures of fetal rat bone were used to test the effects of molecular modification on the bone resorbing activity of the vitamin D 3 metabolites 25 OH D 3 and 1,25 (OH) 2 D 3. Addition of 26 hydroxyl group to the 25 OH D 3 side chain reduced the activity more than 10 fold. Shortening the 25 OH D 3 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) 2D 3 was likewise more active than the vitamin D 3 derivatives with which it was compared. The 3α hydroxy epimer of 1,25 (OH) 2D 3 [1,25 (OH) 2D 3 (3α)] was more than three orders of magnitude less active than 1,25 (OH) 2D 3. 1,24 (R),25 (OH) 3D 3 was approximately 1/10 as active as 1,25 (OH) 2D 3. When the 24 hydroxyl was in the S configuration, the trihydroxy derivative was even less effective. 1,25 (OH) 2D 3 was approximately equiactive with 1,25 (OH) 2D 2. 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 D 3 metabolite or synthetic congener surpasses 1,25 (OH) 2D 3 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.

Original languageEnglish (US)
Pages (from-to)879-886
Number of pages8
JournalMolecular Pharmacology
Volume12
Issue number6
StatePublished - Dec 1 1976

ASJC Scopus subject areas

  • Pharmacology

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