RESUMO
The novel 7-transmembrane receptor MrgX1 is located predominantly in the dorsal root ganglion and has consequently been implicated in the perception of pain. Here we describe the discovery and optimization of a small molecule agonist and initial docking studies of this ligand into the receptor in order to provide a suitable lead and tool compound for the elucidation of the physiological function of the receptor.
Assuntos
Piperazinas/síntese química , Piridazinas/síntese química , Receptores Acoplados a Proteínas G/agonistas , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Cálcio/metabolismo , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Piperazinas/farmacologia , Piridazinas/farmacologia , Receptores Acoplados a Proteínas G/fisiologia , Relação Estrutura-AtividadeRESUMO
High throughput screening led to the discovery of a novel series of 1,3-diaminopropan-2-ol sulfonamides as selective GlyT-1 inhibitors. Structure-activity relationships of this novel series and optimisation of the initial hit that led to the identification of (2), a potent and selective GlyT-1 inhibitor, are also presented.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Humanos , Isomerismo , Conformação Molecular , Ratos , Espectrofotometria Ultravioleta , Relação Estrutura-AtividadeRESUMO
A range of lysine amides 2 to 7 tagged with different combinations of either Raman- and/or infrared (IR)-active groups (4-cyanobenzoyl chloride, 3,5-di-tert-butyl-4-hydroxybenzoic acid, or 4-pentynoic acid) have been synthesized on Sasrin resin. Randomly selected beads of unknown identity were then analyzed by Fourier transform infrared (FTIR) and Raman microspectrometry. Using a combination of these two spectroscopic techniques, the six amide derivatives 2 to 7 and the unfunctionalized lysine template 1 were unambiguously identified from their Raman and FTIR spectra. The potential applications of FTIR and Raman microspectrometry for analysis of organic reactions on solid support and for encoding combinatorial libraries has been demonstrated.
