RESUMO
A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
Assuntos
Adipócitos/efeitos dos fármacos , Benzoatos/síntese química , Proteínas de Ligação a DNA/metabolismo , Oximas/síntese química , Receptores do Ácido Retinoico/agonistas , Fatores de Transcrição/agonistas , Células 3T3 , Adipócitos/metabolismo , Adipócitos/fisiologia , Animais , Benzoatos/química , Benzoatos/metabolismo , Benzoatos/farmacologia , Ligação Competitiva , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Cristalografia por Raios X , Ligantes , Camundongos , Oximas/química , Oximas/metabolismo , Oximas/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/biossíntese , Receptores do Ácido Retinoico/biossíntese , Receptores do Ácido Retinoico/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/metabolismo , Receptores X de Retinoides , Fatores de Transcrição/biossíntese , Fatores de Transcrição/metabolismo , Transfecção , Triglicerídeos/metabolismoRESUMO
Retinoid X receptor (RXR) plays a central role in the regulation of many intracellular receptor signalling pathways and can mediate ligand-dependent transcription, acting as a homodimer or as a heterodimer. Here we identify an antagonist towards RXR homodimers which also functions as an agonist when RXR is paired as a heterodimer to specific partners, including peroxisome proliferator-activated receptor and retinoic acid receptor. This dimer-selective ligand confers differential interactions on the transcription machinery: the antagonist promotes association with TAF110 (TATA-binding protein (TBP)-associated factor 110) and the co-repressor SMRT, but not with TBP, and these properties are distinct from pure RXR agonists. This unique class of RXR ligands will provide a means to control distinct target genes at the level of transcription and allow the development of retinoids with a new pharmacological action.