Modulation of RXR function through ligand design

Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids

Volumn 1821, Issue 1, 2012, Pages 57-69

  Pérez, Efrén ^a   Bourguet, William ^b   Gronemeyer, Hinrich ^c   De Lera, Angel R ^a  

^a UNIVERSITY OF VIGO   (Spain)

^b CENTRE DE BIOCHIMIE STRUCTURALE   (France)

^c INSTITUT DE GÉNÉTIQUE ET DE BIOLOGIE MOLÉCULAIRE ET CELLULAIRE   (France)

Author keywords

LXR RXR heterodimer; PPAR RXR heterodimer; Rexinoid; RXR modulator

Indexed keywords

ANTIOBESITY AGENT; GLUCOSE TRANSPORTER 4; HETERODIMER; LIGAND; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; RETINOID X RECEPTOR ALPHA; RETINOID X RECEPTOR BETA; RETINOID X RECEPTOR GAMMA; TRIACYLGLYCEROL;

CRYSTALLOGRAPHY; DIABETES MELLITUS; ENZYME ACTIVITY; GENETIC TRANSCRIPTION; GLUCOSE TRANSPORT; HEPATOMEGALY; HUMAN; INSULIN RESISTANCE; LIGAND BINDING; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; TRIACYLGLYCEROL BLOOD LEVEL;

ANIMALS; DIABETES MELLITUS; HUMANS; INSULIN RESISTANCE; LIGANDS; MODELS, MOLECULAR; OBESITY; ORPHAN NUCLEAR RECEPTORS; PPAR GAMMA; PROTEIN MULTIMERIZATION; PROTEIN STRUCTURE, TERTIARY; RETINOID X RECEPTORS; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC;

ANIMALIA;

EID: 83255192155     PISSN: 13881981     EISSN: 18792618     Source Type: Journal    
DOI: 10.1016/j.bbalip.2011.04.003     Document Type: Review

References (109)

1. P. Germain, P. Chambon, G. Eichele, R.M. Evans, M.A. Lazar, M. Leid, A.R. de Lera, R. Lotan, D.J. Mangelsdorf, and H. Gronemeyer The pharmacology and classification of the nuclear receptor superfamily. RETINOID X RECEPTORS (RXRs) Pharmacol. Rev. 58 2006 760 772
2. M.F. Boehm, L. Zhang, L. Zhi, M.R. McClurg, E. Berger, M. Wagoner, D.E. Mais, C.M. Suto, P.J.A. Davies, R.A. Heyman, and A.M. Nadzan Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells J. Med. Chem. 38 1995 3146 3155
3. P. Shankaranarayanan, A. Rossin, H. Khanwalkar, S. Alvarez, R. Alvarez, A. Jacobson, A. Nebbioso, A.R. de Lera, L. Altucci, and H. Gronemeyer Growth factor-antagonized rexinoid apoptosis involves permissive PPARγ/RXR heterodimers to activate the intrinsic death pathway by NO Cancer Cell 16 2009 220 231
4. L. Altucci, M.D. Leibowitz, K.M. Ogilvie, A.R. de Lera, and H. Gronemeyer RAR and RXR modulation in cancer and metabolic disease Nat. Rev. Drug Discov. 6 2007 793 810
5. K.T. Liby, M.M. Yore, and M.B. Sporn Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer Nat. Rev. Cancer 7 2007 357 369
6. L. Michalik, J. Auwerx, J.P. Berger, V.K. Chatterjee, C.K. Glass, F.J. Gonzalez, P.A. Grimaldi, T. Kadowaki, M.A. Lazar, S. O'Rahilly, C.N.A. Palmer, J. Plutzky, J.K. Reddy, B.M. Spiegelman, B. Staels, and W. Wahli International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors Pharmacol. Rev. 58 2006 726 741
7. D.D. Moore, S. Kato, W. Xie, D.J. Mangelsdorf, D.R. Schmidt, R. Xiao, and S.A. Kliewer International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor α, farnesoid X receptor β, liver X receptor α, liver X receptor β, and vitamin D receptor Pharmacol. Rev. 58 2006 742 759
8. O. Ziouzenkova, and J. Plutzky Retinoid metabolism and nuclear receptor responses: new insights into coordinated regulation of the PPAR-RXR complex FEBS Lett. 582 2008 32 38
9. A.I. Shulman, and D.J. Mangelsdorf Retinoid X receptor heterodimers in the metabolic syndrome New Engl. J. Med. 353 2005 604 615
10. T. Claudel, M.D. Leibowitz, C. Fiévet, A. Tailleux, B. Wagner, J.J. Repa, G.R. Torpier, J.-M. Lobaccaro, J.R. Paterniti, D.J. Mangelsdorf, R.A. Heyman, and J. Auwerx Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor Proc. Natl. Acad. Sci. USA 98 2001 2610 2615
11. P. Desreumaux, L. Dubuquoy, S. Nutten, M. Peuchmaur, W. Englaro, K. Schoonjans, B. Derijard, B. Desvergne, W. Wahli, P. Chambon, M.D. Leibowitz, J.-F. Colombel, and J. Auwerx Attenuation of colon inflammation through activators of the retinoid X receptor (RRX)/peroxisome proliferator-activated receptor γ (PPARγ) heterodimer J. Experim. Med. 193 2001 827 838
12. B.R. Haugen, D.R. Jensen, V. Sharma, L.K. Pulawa, W.R. Hays, W. Krezel, P. Chambon, and R.H. Eckel Retinoid X receptorγ-deficient mice have increased skeletal muscle lipoprotein lipase activity and less weight gain when fed a high-fat diet Endocrinology 145 2004 3679 3685
13. A.W. Ross, L.M. Bell, P.A. Littlewood, J.G. Mercer, P. Barrett, and P.J. Morgan Temporal changes in gene expression in the arcuate nucleus precede seasonal responses in adiposity and reproduction Endocrinology 146 2005 1940 1947
14. N.S. Brown, A. Smart, V. Sharma, M.L. Brinkmeier, L. Greenlee, S.A. Camper, D.R. Jensen, R.H. Eckel, W. Krezel, P. Chambon, and B.R. Haugen Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse J. Clin. Invest. 106 2000 73 79
15. -/- mutant mice are viable Proc. Natl. Acad. Sci. USA 93 1996 9010 9014
16. T2) in adipocytes Proc. Natl. Acad. Sci. USA 98 2001 224 228
17. A. Chawla, Y.J. Repa, R.M. Evans, and D.J. Mangelsdorf Nuclear receptors and lipid physiology: opening the X-files Science 294 2001 1866 1870
18. J.J. Repa, S.D. Turley, J.-M.A. Lobaccaro, J. Medina, L. Li, K. Lustig, B. Shan, R.A. Heyman, J.M. Dietschy, and D.J. Mangelsdorf Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers Science 289 2000 1524 1529
19. J.R. Schultz, H. Tu, A. Luk, J.J. Repa, J.C. Medina, L. Li, S. Schwendner, S. Wang, M. Thoolen, D.J. Mangelsdorf, K.D. Lustig, and B. Shan Role of LXRs in control of lipogenesis Genes Dev. 14 2000 2831 2838
20. B.M. Stenson, M. Rydén, N. Venteclef, I. Dahlman, A.M.L. Pettersson, A. Mairal, G. Åström, L. Blomqvist, V. Wang, J.W.E. Jocken, K. Clément, D. Langin, P. Arner, and J. Laurencikiene Liver X receptor (LXR) regulates human adipocyte lipolysis J. Biol. Chem. 286 2011 370 379
21. J.M. Lehmann, L.B. Moore, T.A. Smith-Oliver, W.O. Wilkinson, T.M. Willson, and S.A. Kliewer An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ) J. Biol. Chem. 270 1995 12953 12956
22. P. Ferrè The biology of peroxisome proliferator-activated receptors Diabetes 53 2004 S43 S50
23. P.J. Willy, K. Umesono, E.S. Ong, R.M. Evans, R.A. Heyman, and D.J. Mangelsdorf LXR, a nuclear receptor that defines a distinct retinoid response pathway Genes Dev. 9 1995 1033 1045
24. J.M. Lehmann, S.A. Kliewer, L.B. Moore, T.A. Smith-Oliver, B.B. Oliver, J.-L. Su, S.S. Sundseth, D.A. Winegar, D.E. Blanchard, T.A. Spencer, and T.M. Willson Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway J. Biol. Chem. 272 1997 3137 3140
25. R. Mukherjee, P.J.A. Davies, D.L. Crombie, E.D. Bischoff, R.M. Cesario, L. Jow, L.G. Hamann, M.F. Boehm, C.E. Mondon, A.M. Nadzan, J.R. Paterniti, and R.A. Heyman Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists Nature 386 1997 407 410
26. J.M. Lenhard, M.E. Lancaster, M.A. Paulik, J.E. Weiel, J.G. Binz, S.S. Sundseth, B.A. Gaskill, R.M. Lightfoot, and H.R. Brown The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction Diabetologia 42 1999 545 554
27. K.M. Ogilvie, R. Saladin, T.R. Nagy, M.S. Urcan, R.A. Heyman, and M.D. Leibowitz Activation of the Retinoid X Receptor suppresses appetite in the rat Endocrinology 145 2004 565 573
28. T. Yamauchi, H. Waki, J. Kamon, K. Murakami, K. Motojima, K. Komeda, H. Miki, N. Kubota, Y. Terauchi, A. Tsuchida, N. Tsuboyama-Kasaoka, N. Yamauchi, T. Ide, W. Hori, S. Kato, M. Fukayama, Y. Akanuma, O. Ezaki, A. Itai, R. Nagai, S. Kimura, K. Tobe, H. Kagechika, K. Shudo, and T. Kadowaki Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes J. Clin. Inv. 108 2001 1001 1013
29. M.D. Leibowitz, R.J. Ardecky, M.F. Boehm, C.L. Broderick, M.A. Carfagna, D.L. Crombie, J. D'Arrigo, G.J. Etgen, M.M. Faul, T.A. Grese, H. Havel, N.I. Hein, R.A. Heyman, D. Jolley, K. Klausing, S. Liu, D.E. Mais, C.M. Mapes, K.B. Marschke, P.-Y. Michellys, C. Montrose-Rafizadeh, K.M. Ogilvie, B. Pascual, D. Rungta, J.S. Tyhonas, M.S. Urcan, M. Wardlow, N. Yumibe, and A. Reifel-Miller Biological characterization of a heterodimer-selective retinoid X receptor modulator: potential benefits for the treatment of type 2 diabetes Endocrinology 147 2006 1044 1053
30. B.S. Cha, T.P. Ciaraldi, L. Carter, S.E. Nikoulina, S. Mudaliar, R. Mukherjee, J.R. Paterniti Jr., and R.R. Henry Peroxisome proliferator-activated receptor (PPAR) γ and retinoid X receptor (RXR) agonists have complementary effects on glucose and lipid metabolism in human skeletal muscle Diabetologia 44 2001 444 452
31. P.J.A. Davies, S.A. Berry, G.L. Shipley, R.H. Eckel, N. Hennuyer, D.L. Crombie, K.M. Ogilvie, J. Peinado-Onsurbe, C. Fievet, M.D. Leibowitz, R.A. Heyman, and J. Auwerx Metabolic effects of rexinoids: tissue-specific regulation of lipoprotein lipase activity Mol. Pharmacol. 59 2001 170 176
32. Q. Shen, G.W. Cline, G.I. Shulman, M.D. Leibowitz, and P.J.A. Davies Effects of rexinoids on glucose transport and insulin-mediated signaling in skeletal muscles of diabetic (db/db) mice J. Biol. Chem. 279 2004 19721 19731
33. H. Singh Ahuja, S. Liu, D.L. Crombie, M. Boehm, M.D. Leibowitz, R.A. Heyman, C. Depre, L. Nagy, P. Tontonoz, and P.J.A. Davies Differential effects of rexinoids and thiazolidinediones on metabolic gene expression in diabetic rodents Mol. Pharmacol. 59 2001 765 773
34. S. Liu, K.M. Ogilvie, K. Klausing, M.A. Lawson, D. Jolley, D. Li, J. Bilakovics, B. Pascual, N. Hein, M. Urcan, and M.D. Leibowitz Mechanism of selective retinoid X receptor agonist-induced hypothyroidism in the rat Endocrinology 143 2002 2880 2885
35. C.D. Haffner, J.M. Lenhard, A.B. Miller, D.L. McDougald, K. Dwornik, O.R. Ittoop, R.T. Gampe, H.E. Xu, S. Blanchard, V.G. Montana, T.G. Consler, R.K. Bledsoe, A. Ayscue, and D. Croom Structure-based design of potent retinoid X receptor α agonists J. Med. Chem. 47 2004 2010 2029
36. X. Li, P.A. Hansen, L. Xi, R.A.S. Chandraratna, and C.F. Burant Distinct mechanisms of glucose lowering by specific agonists for peroxisomal proliferator activated receptor γ and retinoic acid X receptors J. Biol. Chem. 280 2005 38317 38327
37. R.M. Cesario, K. Klausing, H. Razzaghi, D. Crombie, D. Rungta, R.A. Heyman, and D.S. Lala The rexinoid LG100754 is a novel RXR:PPAR{gamma} agonist and decreases glucose levels in vivo Mol. Endocrinol. 15 2001 1360 1369
38. Y.-L. Liu, M.V. Sennitt, D.C. Hislop, D.L. Crombie, R.A. Heyman, and M.A. Cawthorne Retinoid X receptor agonists have anti-obesity effects and improve insulin sensitivity in Zucker fa/fa rats Int. J. Obesity 24 2000 997 1004
39. D. Chai, B. Wang, L. Shen, J. Pu, X.-K. Zhang, and B. He RXR agonists inhibit high-glucose-induced oxidative stress by repressing PKC activity in human endothelial cells. Free Rad Biol. Med. 44 2008 1334 1347
40. P. Shan, J. Pu, A. Yuan, L. Shen, L. Shen, D. Chai, and B. He RXR agonists inhibit oxidative stress-induced apoptosis in H9c2 rat ventricular cells Biochem. Biophys. Res. Commun. 375 2008 628 633
41. S.I. Sherman, J. Gopal, B.R. Haugen, A.C. Chiu, K. Whaley, P. Nowlakha, and M. Duvic Central hypothyroidism associated with retinoid X receptor-selective ligands New Engl. J. Med. 340 1999 1075 1079
42. J.M. Lenhard, D.K. Croom, J.E. Weiel, and D.A. Winegar HIV protease inhibitors stimulate hepatic triglyceride synthesis Arterioscler. Thromb. Vasc. Biol. 20 2000 2625 2629
43. N. Vu-Dac, P. Gervois, I.P. Torra, J.C. Fruchart, V. Kosykh, T. Kooistra, H.M. Princen, J. Dallongeville, and B. Staels Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids J. Clin. Inv. 102 1998 625 632
44. B.M. Forman The antidiabetic agent LG100754 sensitizes cells to low concentrations of peroxisome proliferator-activated receptor γ ligands J. Biol. Chem. 277 2002 12503 12506
45. P.Y. Michellys, R.A. Ardecky, J.-H. Chen, D.L. Crombie, G.J. Etgen, M.M. Faul, A.L. Faulkner, T.A. Grese, R.A. Heyman, D.S. Karanewsky, K. Klausing, M.D. Leibowitz, S. Liu, D.A. Mais, C.M. Mapes, K.B. Marchske, A. Reifel-Miller, K.M. Ojilvie, D. Rungta, A.W. Thompson, J.S. Tyhonas, and M.F. Boehm Novel (2E,4E,6Z)-7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta-2,4,6-trienoic acid retinoid x receptor modulators are active in models of type 2 diabetes J. Med. Chem. 46 2003 2683 2696
46. P.Y. Michellys, R.A. Ardecky, J.-H. Chen, J. D'Arrigo, T.A. Grese, D.S. Karanewsky, M.D. Leibowitz, S. Liu, D.A. Mais, C.M. Mapes, C. Montrose-Rafizadeh, K.M. Ojilvie, A. Reifel-Miller, D. Rungta, A.W. Thompson, J.S. Tyhonas, and M.F. Boehm Design, synthesis and structure-activity relationship studies of novel 6,7-locked-[7-(2-alkoxy-3,5-dialkylbenzene)-3- methylocta]-2,4,6-trienoic acids J. Med. Chem. 46 2003 4087 4103
47. P.Y. Michellys, J. D'Arrigo, T.A. Grese, D.S. Karanewsky, M.D. Leibowitz, D.A. Mais, C.M. Mapes, A. Reifel-Miller, D. Rungta, and M.F. Boehm Design, synthesis and structure-activity relationship of novel RXR-selective modulators Bioorg. Med. Chem. Lett. 14 2004 1593 1598
48. F. Lalloyer, C. Fievet, S. Lestavel, G. Torpier, J. van der Veen, V. Touche, S. Bultel, S. Yous, F. Kuipers, R. Paumelle, J.-C. Fruchart, B. Staels, and A. Tailleux The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia Arterioscler. Thromb. Vasc. Biol. 26 2006 2731 2737
49. W. Bourguet, M. Ruff, P. Chambon, H. Gronemeyer, and D. Moras Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α Nature 375 1995 377 382
50. P.F. Egea, A. Mitschler, N. Rochel, M. Ruff, P. Chambon, and D. Moras Crystal structure of the human RXRα ligand-binding domain bound to its natural ligand: 9-cis-retinoic acid EMBO J. 19 2000 2592 2601
51. B.P. Klaholz, J.-P. Renaud, A. Mitschler, C. Zusi, P. Chambon, H. Gronemeyer, and D. Moras Conformational adaptation of agonists to the human nuclear receptor RARγ Nat. Struct. Mol. Biol. 5 1998 199 202
52. P.F. Egea, A. Mitschler, and D. Moras Molecular recognition of agonist ligands by RXRs Mol. Endocrinol. 16 2002 987 997
53. W. Bourguet, V. Vivat, J.-M. Wurtz, P. Chambon, H. Gronemeyer, and D. Moras Crystal structure of a heterodimeric complex of raR and RXR ligand-binding domains Mol. Cell 5 2000 289 298
54. S. Svensson, T. Ostberg, M. Jacobsson, C. Norstrom, K. Stefansson, D. Hallen, I.C. Johansson, K. Zachrisson, D. Ogg, and L. Jendeberg Crystal structure of the heterodimeric complex of LXR[alpha] and RXR[beta] ligand-binding domains in a fully agonistic conformation EMBO J. 22 2003 4625 4633
55. J.D. Love, J.T. Gooch, S. Benko, C. Li, L. Nagy, V.K.K. Chatterjee, R.M. Evans, and J.W.R. Schwabe The structural basis for the specificity of retinoid-X-receptor-selective agonists: new insights into the role of helix H12 J. Biol. Chem. 277 2002 11385 11391
56. E. Pérez-Santín, P. Germain, F. Quillard, H. Khanwalkar, F. Rodríguez-Barrios, H. Gronemeyer, A.R. de Lera, and W. Bourguet Modulating retinoid X receptor with a series of (E)-3-[4-Hydroxy-3-(3-alkoxy-5, 5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]acrylic acids and their 4-alkoxy isomers J. Med. Chem. 52 2009 3150 3158
57. V. Nahoum, E. Pérez, P. Germain, F. Rodríguez-Barrios, F. Manzo, S. Kammerer, G. Lemaire, O. Hirsch, C.A. Royer, H. Gronemeyer, A.R. de Lera, and W. Bourguet Modulators of the structural dynamics of RXR to reveal receptor function Proc. Natl. Acad. Sci. USA 104 2007 17323 17328
58. Y. Sato, N. Ramalanjaona, T. Huet, N. Potier, J. Osz, P. Antony, C. Peluso-Iltis, P. Poussin-Courmontagne, E. Ennifar, Y. Mély, A. Dejaegere, D. Moras, and N. Rochel The "Phantom Effect" of the rexinoid LG100754: structural and functional insights PLoS One 5 2010 e15119
59. J. Lu, M.I. Dawson, Q.Y. Hu, Z. Xia, J.D. Dambacher, M. Ye, X.-K. Zhang, and E. Li The effect of antagonists on the conformational exchange of the retinoid X receptor alpha ligand-binding domain Magn. Reson. Chem. 47 2009 1071 1080
60. P. Germain, J. Iyer, C. Zechel, and H. Gronemeyer Co-regulator recruitment and the mechanism of retinoic acid receptor synergy Nature 415 2002 187 192
61. R.T. Gampe, V.G. Montana, M.H. Lambert, A.B. Miller, R.K. Bledsoe, M.V. Milburn, S.A. Kliewer, T.M. Willson, and E. Xu Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors Mol. Cell 5 2000 545 555
62. V. Pogenberg, J.-F. Guichou, V. Vivat-Hannah, S. Kammerer, E. Pérez, P. Germain, A.R. de Lera, H. Gronemeyer, C.A. Royer, and W. Bourguet Characterization of the interaction between RAR/RXR heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies J. Biol. Chem. 280 2005 1625 1633
63. Y. Brelivet, S. Kammerer, N. Rochel, O. Poch, and D. Moras Signature of the oligomeric behaviour of nuclear receptors at the sequence and structural level EMBO Rep. 5 2004 423 429
64. A.I. Shulman, C. Larson, D.J. Mangelsdorf, and R. Ranganathan Structural determinants of allosteric ligand activation in RXR heterodimers Cell 116 2004 417 429
65. A. le Maire, C. Teyssier, C. Erb, M. Grimaldi, S. Alvarez, A.R. de Lera, P. Balaguer, H. Gronemeyer, C.A. Royer, P. Germain, and W. Bourguet A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor Nat. Struct. Mol. Biol. 17 2010 801 807
66. V. Chandra, P. Huang, Y. Hamuro, S. Raghuram, Y. Wang, T.P. Burris, and F. Rastinejad Structure of the intact PPARγ-RXRα nuclear receptor complex on DNA Nature 456 2008 350 356
67. K. Takamatsu, A. Takano, N. Yakushiji, K. Morohashi, K. Morishita, N. Matsuura, M. Makishima, A. Tai, K. Sasaki, and H. Kakuta The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRα/β-dual agonist) ChemMedChem 3 2008 780 787
68. K. Takamatsu, A. Takano, N. Yakushiji, K. Morishita, N. Matsuura, M. Makishima, H.I. Ali, E. Akaho, A. Tai, K. Sasaki, and H. Kakuta Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRα-preferential agonist possessing a sulfonamide moiety ChemMedChem 3 2008 454 460
69. K. Morishita, N. Yakushiji, F. Ohsawa, K. Takamatsu, N. Matsuura, M. Makishima, M. Kawahata, K. Yamaguchi, A. Tai, K. Sasaki, and H. Kakuta Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity Bioorg. Med. Chem. Lett. 19 2009 1001 1003
70. G. Wolf Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor? Nutr. Rev. 64 2006 532 538
71. C. Calléja, N. Messaddeq, B. Chapellier, H. Yang, W. Krezel, M. Li, D. Metzger, B. Mascrez, K. Ohta, H. Kagechika, Y. Endo, M. Mark, N.B. Ghyselinck, and P. Chambon Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes Genes Dev. 20 2006 1525 1538
72. A.R. Moise, S. Alvarez, M. Domínguez, R. Alvarez, M. Golczak, G.P. Lobo, J. von Lintig, A.R. de Lera, and K. Palczewski Activation of retinoic acid receptors by dihydroretinoids Mol. Pharmacol. 76 2009 1228 1237
73. O. Ziouzenkova, G. Orasanu, M. Sharlach, T.E. Akiyama, J.P. Berger, J. Viereck, J.A. Hamilton, G. Tang, G.G. Dolnikowski, S. Vogel, G. Duester, and J. Plutzky Retinaldehyde represses adipogenesis and diet-induced obesity Nat. Med. 13 2007 695 702
74. O. Ziouzenkova, G. Orasanu, G. Sukhova, E. Lau, J.P. Berger, G. Tang, N.I. Krinsky, G.G. Dolnikowski, and J. Plutzky Asymmetric cleavage of {beta}-carotene yields a transcriptional repressor of retinoid X receptor and peroxisome proliferator-activated receptor responses Mol. Endocrinol. 21 2007 77 88
75. A.M. de Urquiza, S. Liu, M. Sjöberg, R.H. Zetterström, W. Griffiths, J. Sjövall, and T. Perlmann Docosahexaenoic Acid, a Ligand for the Retinoid X Receptor in Mouse Brain Science 290 2000 2140 2144
76. M.A. Harmon, M.F. Boehm, R.A. Heyman, and D.J. Mangelsdorf Activation of mammalian retinoid X receptors by the insect growth regulator methoprene Proc. Natl. Acad. Sci. USA 92 1995 6157 6160
77. S. Kitareewan, L. Burka, B. Tomer, C.E. Parker, L.J. Deterding, R.D. Stevens, B.M. Forman, D.E. Mais, R.A. Heyman, T. McMorris, and C. Weinberger Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR Mol. Cell. Biol. 7 1996 1153 1166
78. P.K. LeMotte, S. Keidek, and C.M. Apfel Phytanic acis is a retinoid X receptor ligand Eur. J. Biochem. 236 1996 328 333
79. A.W.M. Zomer, B. van der Burg, G.A. Jansen, R.J.A. Wanders, B.T. Poll-The, and P.T. van der Saag Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferator-activated receptor γ J. Lipid Res. 41 2000 1801 1807
80. H. Kotani, H. Tanabe, H. Mizukami, M. Makishima, and M. Inoue Identification of a naturally occurring rexinoid, honokiol. that activates the retinoid X receptor J. Nat. Prod. 73 2010 1332 1336
81. A.R. de Lera, W. Bourguet, L. Altucci, and H. Gronemeyer Design of selective nuclear receptor modulators: RAR and RXR as a case study Nat. Rev. Drug Discov. 6 2007 811 820
82. M.F. Boehm, L. Zhang, B.A. Badea, S.K. White, D.E. Mais, E. Berger, C.M. Suto, M.E. Goldman, and R.A. Heyman Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids J. Med. Chem. 37 1994 2930 2941
83. R.L. Beard, D.W. Gil, D.K. Marler, E. Henry, D.F. Colon, S.J. Gillett, T. Arefieg, T.S. Breen, H. Krauss, P.J.A. Davies, and R.A.S. Chandraratna Structural basis for the differential RXR & RAR activity of stilbene retinoid analogs Bioorg. Med. Chem. Lett. 4 1994 1447 1452
84. R.L. Beard, R.A.S. Chandraratna, D.F. Colon, S.J. Gillett, E. Henry, D.K. Marler, T. Song, L. Denys, M.E. Garst, T. Arefieg, E. Klien, D.W. Gil, D.M. Wheeler, D.M. Kochhar, and P.J.A. Davies Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids J. Med. Chem. 38 1995 2820 2829
85. L. Ouamrane, G. Larrieu, B. Gauthier, and T. Pineau RXR activators molecular signalling: involvement of a PPARα-dependent pathway in the liver and kidney, evidence for an alternative pathway in the heart Brit. J. Pharmacol. 138 2003 845 854
86. S.S. Canan-Koch, L.J. Dardashti, R.M. Cesario, G.E. Croston, M.F. Boehm, R.A. Heyman, and A.M. Nadzan Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells J. Med. Chem. 42 1999 742 750
87. M.M. Faul, A.M. Ratz, K.A. Sullivan, W.G. Trankle, and L.L. Winneroski Synthesis of novel retinoid X receptor-selective retinoids J. Org. Chem. 66 2001 5772 5782
88. J.M. Way, W.W. Harrington, K.K. Brown, W.K. Gottschalk, S.S. Sundseth, T.A. Mansfield, R.K. Ramachandran, T.M. Willson, and S.A. Kliewer Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor γ activation has coordinate effects on gene expression in multiple insulin-sensitive tissues Endocrinology 142 2001 1269 1277
89. G.V. Martin, H.L.V. Poirier, N. Hennuyer, D. Crombie, J.C. Fruchart, R.A. Heyman, P. Besnard, and J. Auwerx Induction of the fatty acid transport protein 1 and acyl-coa synthase genes by dimer-selective rexinoids suggests that the peroxisome proliferator-activated receptor-retinoid X receptor heterodimer is their molecular target J. Biol. Chem. 275 2000 12612
90. R. Mukherjee, J. Strasser, L. Jow, P. Hoener, J.R. Paterniti Jr., and R.A. Heyman RXR agonists activate pparα-inducible genes, lower triglycerides, and raise HDL levels in vivo Arterioscler. Thromb. Vasc. Biol. 18 1998 272 276
91. M.I. Dawson Synthetic retinoids and their nuclear receptors Curr. Med. Chem. Anticancer Agents 4 2004 199 230
92. C.M. Apfel, M. Kamber, M. Klaus, P. Mohr, S. Keidel, and P.K. LeMotte Enhancement of HL-60 differentiation by a new class of retinoids with selective activity on retinoid X receptor J. Biol. Chem. 270 1995 30765 30772
93. P.E. Macchia, P. Jiang, Y.-D. Yuan, R.A.S. Chandarartna, R.E. Weiss, O. Chassande, J. Samarut, S. Refetoff, and C.F. Burant RXR receptor agonist suppression of thyroid function: central effects in the absence of thyroid hormone receptor Am. J. Physiol. Endocrinol. Metab. 283 2002 E326 E331
94. T. Deng, S. Shan, Z.-B. Li, Z.-W. Wu, C.-Z. Liao, B. Ko, X.-P. Lu, J. Cheng, and Z.-Q. Ning A new retinoid-like compound that activates peroxisome proliferator-activated receptors and lowers blood glucose in diabetic mice Biol. Pharm. Bull. 28 2005 1192 1196
95. S.S. Canan Koch, L.J. Dardashti, J.J. Hebert, S.K. White, G.E. Croston, K.S. Flatten, R.A. Heyman, and A.M. Nadzan Identification of the first retinoid x receptor homodimer antagonist J. Med. Chem. 39 1996 3229 3234
96. I.G. Schulman, C. Li, J.W. Schwabe, and R.M. Evans The phantom ligand effect: allosteric control of transcription by the retinoid X receptor Genes Dev. 11 1997 299 308
97. H. Umemiya, H. Fukasawa, M. Ebisawa, L. Eyrolles, E. Kawachi, G. Eisenmann, H. Gronemeyer, Y. Hashimoto, K. Shudo, and H. Kagechika Regulation of retinoidal actions by diazepinylbenzoic acids. retinoid synergists activate the RXR-RAR heterodimers J. Med. Chem. 40 1997 4222 4234
98. B. Takahashi, K. Ohta, E. Kawachi, H. Fukasawa, Y. Hashimoto, and H. Kagechika Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimers J. Med. Chem. 45 2002 3327 3329
99. T. Yotsumoto, T. Naitoh, T. Kanaki, and N. Tsuruzoe A retinoid X receptor antagonist, HX531, improves leptin resistance without increasing plasma leptin level in KK-Ay mice under normal dietary conditions Metabolism 54 2005 573 578
100. J. Sakaki, M. Kishida, K. Konishi, H. Gunji, A. Toyao, Y. Matsumoto, T. Kanazawa, H. Uchiyama, H. Fukaya, H. Mitani, Y. Arai, and M. Kimura Synthesis and structure-activity relationship of novel RXR antagonists: orally active anti-diabetic and anti-obesity agents Bioorg. Med. Chem. Lett. 17 2007 4804 4807
101. J. Sakaki, K. Konishi, M. Kishida, H. Gunji, T. Kanazawa, H. Uchiyama, H. Fukaya, H. Mitani, and M. Kimura Synthesis and structure-activity relationship of RXR antagonists based on the diazepinylbenzoic acid structure Bioorg. Med. Chem. Lett. 17 2007 4808 4811
102. K. Ohta, M. Tsuji, E. Kawachi, H. Fukasawa, Y. Hashimoto, K. Shudo, and H. Kagechika Potent retinoid synergists with a diphenylamine skeleton Biol. Pharm. Bull. 21 1998 544 546
103. T. Nishimaki-Mogami, N. Tamehiro, Y. Sato, K.-I. Okuhira, K. Sai, H. Kagechika, K. Shudo, S. Abe-Dohmae, S. Yokoyama, Y. Ohno, K. Inoue, and J.-I. Sawada The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines Biochem. Pharmacol. 76 2008 1006 1013
104. F. Ohsawa, K.-I. Morishita, S. Yamada, M. Makishima, and H. Kakuta Modification at the lipophilic domain of RXR agonists differentially influences activation of RXR heterodimers ACS Med. Chem. Lett. 1 2010 521 525
105. B. Lagu, B. Pio, R. Lebedev, M. Yang, and P.D. Pelton RXR-LXR heterodimer modulators for the potential treatment of dyslipidemia Bioorg. Med. Chem. Lett. 17 2007 3497 3503
106. B. Lagu, R. Lebedev, B. Pio, M. Yang, and P.D. Pelton Dihydro-[1H]-quinolin-2-ones as retinoid X receptor (RXR) agonists for potential treatment of dyslipidemia Bioorg. Med. Chem. Lett. 17 2007 3491 3496
107. V. Miller, F. Benedetti, J. Rigas, A. Verret, D. Pfister, D. Straus, M. Kris, M. Crisp, R. Heyman, G. Loewen, J. Truglia, and R. Warrell Initial clinical trial of a selective retinoid X receptor ligand, LGD1069 J. Clin. Oncol. 15 1997 790 795
108. S. Bershad, A. Rubinstein, J.R. Paterniti, N.-A. Le, S.C. Poliak, B. Heller, H.N. Ginsberg, R. Fleischmajer, and W.V. Brown Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne N. Engl. J. Med. 313 1985 981 985
109. J.A. Pinaire, and A. Reifel-Miller Therapeutic potential of rexinoid X receptor modulators for the treatment of the metabolic syndrome PPAR Res. 2007 Article ID 94156.