RESUMEN
Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Dibenzazepinas/farmacología , Receptores de Glucocorticoides/agonistas , Tiadiazoles/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/genética , Glucemia , Dibenzazepinas/uso terapéutico , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Cinética , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Ratones , Simulación del Acoplamiento Molecular , Prednisolona/farmacología , Prednisolona/uso terapéutico , Unión Proteica , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/metabolismo , Tiadiazoles/uso terapéuticoRESUMEN
A series of 1,3-diazacycloalkyl carboxaldehyde oxime derivatives was synthesized and tested for muscarinic activity in receptor binding assays using [3H]-oxotremorine-M (OXO-M) and [3H]-pirenzepine (PZ) as ligands. Potential muscarinic agonistic or antagonistic properties of the compounds were determined using binding studies measuring their potencies to inhibit the binding of OXO-M and PZ. Preferential inhibition of OXO-M binding was used as an indicator for potential muscarinic agonistic properties; this potential was confirmed in functional studies on isolated organs.
