Retinoic acid receptor ligands

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). 

Bachmair F, Hoffmann R, Daxenbichler G, and Langer T (2000) Studies on structure-activity relationships of retinoic acid receptor ligands hy means of molecular modeling. Vitamins and Hormones 59, 159-215. 

Blumberg B, Bolado J Jr., Derguini F, Craig AG, Moreno TA, Chakravarti D, Heyman RA, Buck J, and Evans RM (1996) Novel retinoic acid receptor ligands inXenopus embryos. Proceedings of the National Academy of Sciences of the USA 93,4873-8. 

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. 

Bachmair F, Hoffmann RD, Daxenbichler G, Langer T. Studies of structure activity relationship of retinoic acid receptor ligands by means of molecular modeling. Vitam Horm 2000 59 159-215. 

The mechanisms of corticosteroid receptor regulation of transcription have been elucidated. Both type I and type II corticosteroid receptors are members of a superfamily of ligand-activated transcription factors defined by protein sequence similarity. Included in this superfamily are various other steroid receptors, such as the estrogen receptor, as well as members of the retinoic acid receptor... 

In another recent example, Hashimoto reported photoaffinity experiments on retinoic acid receptors (RAR). Retinoic acid plays a critical role in cell proliferation and differentiation. RARs belong to the superfamily of nuclear/ thyroid hormone receptors. They consist of six transmembrane domains (A-F) which is a general feature of these receptors. The A/B domains have an autonomous transactivation function while the C-domain contains the Zn-finger, which binds to DNA. The large E-domain participates in ligand binding, dimerization, and ligand dependent transactivation. Finally, D- and F-domains help the orientation and stabilization of the E-domain. 

In addition to the receptors mentioned in A, the family of steroid receptors also includes the product of the oncogene erb-A (see p. 398), the receptor for the environmental toxin dioxin, and other proteins for which a distinct hormone ligand has not been identified (known as orphan receptors ). Several steroid receptors—e. g., the retinoic acid receptor-form functional heterodimers with orphan receptors. 

Vitamin A is essential for growth and development of cells and tissues. In its active form, retinoic acid (RA), it controls the regular differentiation as a ligand for retinoic acid receptors (RAR, RXR) and is involved in the integration (gap junction formation) of cell formations (Biesalski, 1996 Biesalski et al, 1999). Vitamin A plays a substantial role, especially in the respiratory epithelium and the lung. During moderate vitamin A deficiency, the incidence for diseases of the respiratory tract is considerably increased and repeated respiratory infections can be influenced therapeutically by a moderate vitamin A supplementation (Biesalski et ah, 2001 Greenberg et ah, 1997 John et ah, 1997). 

The PPAR-RXR complex binds to specific DNA response elements (PPREs composed of two hexanucleotide direct repeats) in gene promoters and functions as a transcription factor, which can be activated by either RXR- or PPAR-specific ligands. The consensus site for PPAR-RXR binding is a direct repeat of two -AGGTCA- sequences with a single nucleotide spacer (a DR1 response element). However, DR1 elements may also bind other complexes, including RAR (retinoic acid receptor)/RXR heterodimers and RXR homodimers (25). Further specificity for binding of PPARs may be provided by sequences that flank the DR1 site (26). 

Figure 29-6. Gene transcription is regulated by retinoic acid.Ah-Zrwm-retinoic acid and 9-cA-retinoic acid are ligands for retinoic acid receptors (RARs) and retinoid X receptors (RXRs), respectively. The RXRs can form heterodimers with RARs and with the thyroid hormone receptors (TRs), the vitamin D receptor (VDR), and the peroxisome proliferator-activated receptors (PPARs) and a number of other hormone- and nutrient-responsive transcription factors to moderate gene transcription. Because of the ability of RXR to form heterodimers with other nuclear receptors, vitamin A has abroad effect on many hormonally and nutrient-responsive genes.

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. 

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. 

Natural variations in nuclear receptors reinforce the idea that nuclear receptors are good candidates for the creation of orthogonal ligand-receptor pairs. For example, the human retinoic acid receptor (RAR) has three subtypes RARa, RAR/ and RARy. These three subtypes differ at 87 amino acids but have only three divergent residues in the binding pocket [11] (Tab. 8.1). However, these three divergent residues are responsible for different binding profiles of synthetic retinoids... 

GiguereV (1994) Retinoic acid receptors. In Vitamin Receptors Vitamins and Ligands in Cell Communication, K Daksbinamurti (ed.), Cambridge, UK Cambridge University Press. 

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