TY - JOUR 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 <em>in Vitro</em> JF - Molecular Pharmacology JO - Mol Pharmacol SP - 879 LP - 886 VL - 12 IS - 6 AU - PAULA H. STERN AU - THALIA MAVREAS AU - CLARENCE L. TRUMMEL AU - HEINRICH K. SCHNOES AU - HECTOR F. DELUCA Y1 - 1976/11/01 UR - http://molpharm.aspetjournals.org/content/12/6/879.abstract N2 - 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. ER -