Biological activity of the C-1, C-3, C-25, β-D-glucopyranosides of 1,25-dihydroxyvitamin D₃

We have shown previously that the 3-β-D-glucopyranosides of vitamin D₃, 1α-hydroxyvitamin D₃, 1,25-dihydroxyvitamin D₃ and 25-hydroxyvitamin D₃ are biologically active in vivo. In order to determine whether the presence of the β-D-glucopyranoside moiety linked to either the C-3, the C-25 or the C-1 hydroxyl function of the molecule affected the biological activity of the conjugates 1, 2, or 3 derived from 1,25-dihydroxyvitamin D₃, we administered increasing amounts of compounds to vitamin D-deficient rats maintained on a low calcium diet. The aglycone, 1,25-dihydroxvitamin D₃ (4), also was administered to another group of such animals. When administered i.v., all three β-D-glucopyranosides increased intestinal calcium transport in doses as low as 50 pmol/rat. A dose of ~500 pmol/rat was required to increase bone calcium mobilization in these same animals. The three glucosides were found to be equally active in both biological responses. A dose of only 5 pmol of 1,25-dihydroxyvitamin D₃ (4) increased both intestinal calcium transport and bone calcium mobilization. We also performed similar experiments after the p.o. administration of these compounds to vitamin D-deficient rats maintained on a low calcium diet. The glucopyranosides 1, 2 and 3 were able to increase calcium transport in the intestine, as well as mobilize bone calcium at doses of between 500 and 5000 pmol/rat. Once again, the compounds were equipotent, but were less active than 1,25-dihydroxyvitamin D₃ (4). After the i.v. or p.o. doses of the glucosides, plasma concentrations of 1,25-dihydroxyvitamin D₃ increased in a dose-dependent manner. We conclude that: 1) The C-3, C-25 and C-1 β-D-glucopyranosides of 1,25-dihydroxyvitamin D₃ are biologically active and equipotent in vivo, most likely as a result of hydrolysis to the free aglycone and 2) they are less active than the aglycone in this respect.