RESUMEN
Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium- and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radioligand binding interaction studies revealed that the full agonists do not bind to the same site as the partial agonists but exhibit positive heterotropic cooperativity. Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo. Furthermore, the endogenous fatty acid docosahexaenoic acid (DHA) shows negative or neutral cooperativity with members of both series of agonists in binding assays but displays positive cooperativity in functional assays. Another synthetic agonist is allosteric with members of both agonist series, but apparently competitive with DHA. Therefore, there appear to be three allosterically linked binding sites on FFA1 with agonists specific for each of these sites. Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation. These ligands with their high potencies and strong positive functional cooperativity with endogenous fatty acids, demonstrated in vitro and in vivo, have the potential to deliver therapeutic benefits.
Asunto(s)
Hipoglucemiantes/farmacología , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Sitio Alostérico , Animales , Arginina/genética , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Línea Celular , Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/farmacología , Agonismo Parcial de Drogas , Sinergismo Farmacológico , Prueba de Tolerancia a la Glucosa , Humanos , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutación , Fenilpropionatos/química , Fenilpropionatos/farmacología , Ensayo de Unión Radioligante , Receptores Acoplados a Proteínas G/genética , Relación Estructura-ActividadRESUMEN
Structural modification of a series of dual LXRα/ß agonists led to the identification of a new class of LXRß partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRß with a reversed orientation compared to 1.
Asunto(s)
Receptores Nucleares Huérfanos/agonistas , Isoformas de Proteínas/agonistas , Pirroles/síntesis química , Sitios de Unión , Células CACO-2 , Cristalografía por Rayos X , Genes Reporteros , Células HEK293 , Humanos , Receptores X del Hígado , Receptores Nucleares Huérfanos/química , Unión Proteica , Isoformas de Proteínas/química , Pirroles/farmacología , Relación Estructura-Actividad , TransfecciónRESUMEN
The generation of vinyl or aryl radicals under classical, thermal AIBN/n-Bu(3)SnH conditions at 80 degrees C in the presence of an excess of (MeO)(3)P gives rise to the corresponding vinyl- or arylphosphonates in good yields. This approach complements the photochemical reactions of the same systems previously used. Reactions with the individual stereoisomers of MeCH=CHMeBr (thermal AIBN/n-Bu(3)SnH conditions) afford a radical-equilibrated 96/4 E/Z ratio of vinylphosphonates. Substitution of (TMS)(3)SiH for n-Bu(3)SnH yields an approximately 1/1 ratio of separable E and Z vinylphosphonate diastereomers.