Molecular evaluation of vitamin D-3 receptor agonists designed for topicaltreatment of skin diseases

MC903 (calcipotriol) is a synthetic, low calcemic analog of the nuclear hor mone 1 alpha ,25-dihydroxyvitamin D-3 and used in the treatment of psoriasi s. The beneficial effects of MC903 on psoriasis are based on gene regulator y events. The genomic actions of 1 alpha ,25-dihydroxyvitamin D-3 and its a nalogs are primarily mediated by a complex of the vitamin D-3 receptor and the retinoid X receptor bound to a 1 alpha ,25-dihydroxyvitamin D-3 respons e element that can be considered as the molecular switch of 1 alpha ,25-dih ydroxyvitamin D-3 signaling. In this study, the interaction of MC903 and tw o new analogs, GS1500 and EB1213, with this molecular switch was compared w ith that of 1 alpha ,25-dihydroxyvitamin D-3. In DNA-dependent limited prot ease digestion assays, ligand-dependent gel shift assays and mammalian-one- hybrid assays, all four ligands appeared to be equally sensitive VDR agonis ts that activated vitamin D-3 receptor-retinoid X receptor-1 alpha ,25-dihy droxyvitamin D-3 response element complexes at a concentration of approxima tely 0.2 nM. The analyzed VDR agonists, however, also showed individual mol ecular properties, such as a reduced sensitivity in HaCaT cells (MC903), a selectivity for DNA-bound vitamin D-3 receptor-retinoid X receptor heterodi mers (GS1500) and a long-lasting stabilization of vitamin D-3 receptor-reti noid X receptor-1 alpha ,25-dihydroxyvitamin D-3 response element complexes (EB1213). This molecular evaluation demonstrated that the sensitivity in a ctivating the vitamin D3 receptor is already optimal for MC903, but the ana log may not be ideal in keeping the receptor active and in selectively trig gering 1 alpha ,25-dihydroxyvitamin D-3 signaling pathways.