RESUMO
A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (K(i(CAP)) = 0.2 nM; IC(50(pH)) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region.
Assuntos
Analgésicos/síntese química , Piridinas/síntese química , Sulfonamidas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/química , Analgésicos/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Células CHO , Capsaicina/farmacologia , Cricetinae , Cricetulus , Dopamina/análogos & derivados , Dopamina/farmacologia , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Neuralgia/tratamento farmacológico , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Canais de Cátion TRPV/genéticaRESUMO
The structure-activity relationships of N-(3-acyloxy-2-benzylpropyl)-N'-4-[(methylsulfonylamino)benzyl] thioureas, which represent simplified RTX-based vanilloids, were investigated by varying the distances between the four principal pharmacophores and assessing binding and antagonistic activity on rTRPV1. The analysis indicated that a 3-pivaloyloxy-2-benzylpropyl C-region conferred the best potency in binding affinity and antagonism. The molecular modeling of this best template with the tetrameric homology model of rTRPV1 was performed to identify its binding interactions with the receptor.
Assuntos
Simulação de Dinâmica Molecular , Canais de Cátion TRPV/antagonistas & inibidores , Tioureia/química , Animais , Sítios de Ligação , Células CHO , Cricetinae , Cricetulus , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/metabolismo , Tioureia/síntese químicaRESUMO
On the basis of the previous lead N-4-t-butylbenzyl 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamide (3) as a potent TRPV1 antagonist, structure-activity relationships for the B (propanamide part) and C-region (4-t-butylbenzyl part) have been investigated for rTRPV1 in CHO cells. The B-region was modified with dimethyl, cyclopropyl and reverse amides and then the C-region was replaced with 4-substituted phenyl, aryl alkyl and diaryl alkyl derivatives. Among them, compound 50 showed high binding affinity with K(i)=21.5nM, which was twofold more potent than 3 and compound 54 exhibited potent antagonism with K(i(ant))=8.0nM comparable to 3.
Assuntos
Analgésicos/química , Analgésicos/farmacologia , Mesilatos/química , Mesilatos/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Humanos , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
Structure-activity relationships for the A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the (S)-configuration (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency.