RESUMO
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
Assuntos
Amidas/química , Amidas/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bovinos , Biologia Computacional , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Enxofre/químicaRESUMO
A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
Assuntos
Amidas/farmacologia , Compostos de Bifenilo/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Anilidas/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Humanos , Estrutura Molecular , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
Melanin-concentrating hormone (MCH) is a critical hypothalamic anabolic neuropeptide, with key central and peripheral actions on energy balance regulation. The actions of MCH are, so far, known to be transduced through two seven-transmembrane-like receptor paralogues, named MCH1R and MCH2R. MCH2R is not functional in rodents. MCH1R is an important receptor involved in mediating feeding behaviour modulation by MCH in rodents. Pharmacological antagonism at MCH1R in rodents diminishes food intake and results in significant and sustained weight loss in fat tissues, particularly in obese animals. Additionally, MCH1R antagonists have been shown to have anxiolytic and antidepressant properties. The purpose of this review is to highlight the recent numerous pieces of evidence showing that pharmacological blockade at MCH1R could be a potential treatment for obesity and its related metabolic syndrome, as well as for various psychiatric disorders.
