RESUMEN
The structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism compared to the prototype antagonist.
Asunto(s)
Sulfonamidas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Tiourea/análogos & derivados , Tiourea/farmacología , Animales , Células CHO , Calcio/metabolismo , Cricetinae , Ligandos , Estructura Molecular , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Canales Catiónicos TRPV/metabolismo , Tiourea/químicaRESUMEN
The structure-activity relationships for the 'B-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. A docking model of potent antagonist 2 with the sensor region of TRPV1 is proposed.
Asunto(s)
Sulfonamidas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Tiourea/análogos & derivados , Tiourea/farmacología , Animales , Células CHO , Cricetinae , Ligandos , Modelos Moleculares , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Sulfonamidas/química , Canales Catiónicos TRPV/química , Canales Catiónicos TRPV/metabolismo , Tiocarbamatos/síntesis química , Tiocarbamatos/química , Tiourea/químicaRESUMEN
Isosteric replacement of the phenolic hydroxyl group in potent vanilloid receptor (VR1) agonists with the alkylsulfonamido group provides a series of compounds which are effective antagonists to the action of the capsaicin on rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells. In particular, compound 61, N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N'-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea was a full antagonist against capsaicin, displayed a K(i) value of 7.8 nM (compared to 520 nM for capsazepine and 4 nM for 5-iodoRTX), and showed excellent analgesic activity in mice. Structure-activity analysis of the influence of modifications in the A- and C-regions of 4-methylsulfonamide ligands on VR1 agonism/antagonism indicated that 3-fluoro substitution in the A-region and a 4-tert-butylbenzyl moiety in the C-region favored antagonism, whereas a 3-methoxy group in the A-region and 3-acyloxy-2-benzylpropyl moieties in the C-region favored agonism.