RT Journal Article SR Electronic T1 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 JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 879 OP 886 VO 12 IS 6 A1 PAULA H. STERN A1 THALIA MAVREAS A1 CLARENCE L. TRUMMEL A1 HEINRICH K. SCHNOES A1 HECTOR F. DELUCA YR 1976 UL http://molpharm.aspetjournals.org/content/12/6/879.abstract AB 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.