Molecular Pharmacology, Vol 12, 879-886, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

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

¹ Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611
² Department of Pharmacology and Toxicology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14620
³ Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706

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 3-hydroxy epimer of 1,25-(OH)₂D₃ [1,25-(OH)₂D₃ (3)] 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.

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