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Comparison of 6-s-cis- and 6-s-trans-Locked Analogs of 1,25-Dihydroxyvitamin D₃ Indicates That the 6-s-cis Conformation Is Preferred for Rapid Nongenomic Biological Responses and That Neither 6-s-cis- nor 6-s-trans-Locked Analogs Are Preferred for Genomic Biological Responses

Division of Biomedical Sciences (A.W.N.), Departments of Biochemistry (A.W.N., J.E.B., M.C.D., M.C.F-C.) and Chemistry (W.H.O., M.W.H.), University of California, Riverside, California 92521,
Laboratorium voor Experimentele Geneeskunde en Endocrinologie (R.B., H.v.B.), Katholieke Universiteit Leuven, Leuven B-3000, Belgium,
Department of Basic Sciences (A.L.R., E.D., R.K., M.C.F-C.), University of Texas Dental Branch, Houston, Texas 77030

The hormone 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] generates biological responses via both genomic and rapid, nongenomic mechanisms. The genomic responses utilize signal transduction pathways linked to a nuclear receptor (VDR_nuc) for 1,25(OH)₂D₃, while the rapid responses are believed to utilize other signal transduction pathways that may be linked to a putative membrane receptor for 1,25(OH)₂D₃. The natural seco steroid is capable of facile rotation about its 6,7 single carbon bond, which permits generation of a continuum of potential ligand shapes extending from the 6-s-cis (steroid like) to the 6-s-trans (extended). To identify the shape of conformer(s) that can serve as agonists for the genomic and rapid biological responses, we measured multiple known agonist activities of two families of chemically synthesized analogs that were either locked in the 6-s-cis (6C) or 6-s-trans (6T) conformation. We found that 6T locked analogs were inactive or significantly less active than 1,25(OH)₂D₃ in both rapid responses (transcaltachia in perfused chick intestine, ⁴⁵Ca²⁺ influx in ROS 17/2.8 cells) and genomic (osteocalcin induction in MG-63 cells, differentiation of HL-60 cells, growth arrest of MCF-7 cells, promoter transfection in COS-7 cells) assays. In genomic assays, 6C locked analogs bound poorly to the VDR_nuc and were significantly less effective than 1,25(OH)₂D₃ in the same series of assays designed to measure genomic responses. In contrast, the 6C locked analogs were potent agonists of both rapid response pathways and had activities equivalent to the conformationally flexibile 1,25(OH)₂D₃; this represents the first demonstration that 6-s-cis locked analogs can function as agonists for vitamin D responses.

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