Retinoic selective ligands

Roalsvig, X, Honeyman, J.A., Tortola-Ni, D.R., Reczek, P. R., Mansuri, M.M., Starrett, J.E., Jr. Retinoic acid receptor beta,gamma-selective ligands synthesis and biological activity of 6-substituted 2-naphthoic add retinoids. J. Med. Chem. 

Roy, B., Taneja, R., and Chambon, P. (1995). Synergistic activation of retinoic acid (RA)-re-sponsive genes and induction of embryonal carcinoma ceU differentiation by an RA receptor a (RARa)-, RARP-, or RARy-selective ligand in combination vdth a retinoid X receptor-specific ligand. Mol. Cell. Biol. 15, 6481-6487. 

Shaw, N., M. Elholm, and N. Noy. 2003. Retinoic Acid Is a High Affinity Selective Ligand for the Peroxisome Prohferator-Activated Receptor p/8. J Biol Chem 278, no 43 41589-92. 

Yu K-L, Ostrowski J, Chen S, Tramposch KM, Reczek PR, Mansuri MM and Starred JE Jr (1996) Stmctural modifications of 6-naphthalene-2-carboxylate retinoids. Bioorg Med Chem Lett 6 2865-2870 Yu KL, Spinazze P, Ostrowski J, Currier SJ, Pack EJ, Hanuner L, Roalsvig T, Honeyman JA, Tortolani DR, Reczek PR et al (1996) Retinoic acid receptor p,y-selective ligands Synthesis and biological activity of 6-sub-stituted 2-naphthoic acid retinoids. 7 Chem 39 2411-2421... 

H. M. M. Arafa, E. M. A. Hamada, M. M. A. Elzamai and H. Nau, Eully automated detemination of selective retinoic acid receptor ligands in mouse plasma and tissue by reversed-phase liquid chi omatography coupled on-line with solid-phase extraction , 7. Chromatogr. A 729 125-136 (1996). 

European researchers found recently that retinoic acid-induced apoptosis in leukemia cells was mediated by paracrine action of tumor-selective death ligand trail (tumor necrosis factor-related apoptosis-inducing ligand) [4]. 

Tissues contain two types of receptors for 1,25-dihydroxyvitamin D a classic steroid hormone nuclear receptor and a putative membrane receptor. 1,25-Dihydroxyvitamin D interacts with the nuclear receptor to form a receptor-ligand complex (Fig. 30-4). This complex then interacts with other nuclear proteins, such as the retinoic acid receptor (RXR) to form a functional transcription complex. The main effect of this transcription complex is to alter the amount of mRNAs coding for selected proteins such as cal-bindin, the calcium transport protein in the intestine, and the vitamin D receptor. In concert with PTH, 1,25-dihydroxyvitamin D acts to mobilize calcium from bone.As a consequence, serum calcium and phosphate homeostasis is maintained by a combination of 1,25-dihydroxyvitamin D stimulation of intestinal absorption and bone turnover. 

Beimani, Y.L., Marron, K.S., Mais, D.E., Flatten, K., Nadzan, A.M., and Boehm, M.F., Synthesis and characterization of a highly potent and selective isotopically labeled retinoic acid receptor ligand, ALRT1550, J. Org. Chem., 63, 543, 1998. 

High-pressure FTIR measurements in 2003 [97] indicated that C H 0 bonds help stabilize p-sheets. These interactions were also instrumental in the formation of extended p-strands in a chain containing D-chiral residues [98], A helical hairpin motif was attributed [99] to CH- -O bonds between the side chains of one helix and the backbone of another in 2001. The large number (75) of CH O bonds exceeds the 49 conventional intersubunit H-bonds, indicating that the former contacts determine association and orientation of transmembrane helices in PSI [100]. A detailed survey [101] indicated that these bonds can affect the Trp rotation angle in proteins. These bonds were considered potentially as a driving force for ligand selectivity, as noted in the hydrophobic pocket of retinoic add receptor RARy [102]. 

The pleiotropic nature of RA effects suggested an inherent complexity of retinoid signaling pathway(s) that may involve multiple retinoid receptors and ligands. Subsequent discoveries of two other RAR genes (RAR and y) and their isoforms (24-31), as well as three different retinoid-X receptor (RXR) genes (a, j8, and 7)—which encode proteins that selectively bind 9-c w-retinoic acid (32,33) and heterodimerize with RARs and some nonretinoid nuclear receptors (34-36)—proved this hypothesis to be correct. 

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