Structural Requirements for Receptor Binding

Available data on receptor/vitamin D interaction support the general conclusion that affinity for the receptor is determined primarily by the spatial arrangement of the hydroxy functions of the ligand, and that among the three hydroxy groups of la,25-(OH)2D3, those at C-1 and C-25 exert the most profound effect. The data shown in Fig. 11 offer dramatic confirmation of this general statement 1o,25-(OH)2D3 (13g), the active metabolite in intestine, exhibits highest 

Relative ability of vitamin D metabolites and structural analogs to compete with 1,25-(0H)2 23,24- H1D3 for the receptor for 1,2S-(0H)2D3 in chick intestinal cytosol. The log of the ratio of moles/liter of analog over the moles/liter of l,25-(OH)2 l H]D3 required for 50% displacement of the from the receptor is plotted 

In the presence of a 25-hydroxy group, the introduction of an additional hydroxy group into the side chain at either C-24 or C-26 leads to a significant re- 

The effect of 3-hydroxy stereochemistry on binding has not yet been investigated, although suitable models, e. g. la-OH-3-epi-D3 (16a) are available  

The importance of the 1 -hydroxy group is also exemplified by the relatively good binding interaction of certain triene-modified derivatives. For example, 5,6-frans-25-OH-D3 [(5g) see Fig. 11 ] and 25-OH-DHT3(10g) (-500 and 100 times, respectively, less active than la,25-(OH)2D3), are effective U ds, presumably by virtue of the 180 -rotation of ring A which transposes the C-3jJ-hydroxy function into a pseudo-la-hydroxy substituent. The fifty-fold difference in binding of 3-deoxy-la,25-(OH)2D3 (17a)(ca. 1/10 of la,25-(OH)2D3) and 5,6-trans- 

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The structure-activity relationships of thyroid hormones and related structural analogs have been studied using both qualitative and quantitative methods, including the Hansch correlation. The structural requirements for receptor binding, and therefore hormone activity, are ... 

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