RESUMO
The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.
Assuntos
Medição da Dor/métodos , Canal de Cátion TRPA1/agonistas , Canal de Cátion TRPA1/metabolismo , Sequência de Aminoácidos , Animais , Feminino , Células HEK293 , Humanos , Ligantes , Masculino , Medição da Dor/efeitos dos fármacos , Estrutura Secundária de Proteína , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Canal de Cátion TRPA1/químicaRESUMO
The advancement of a series of ligand efficient 2-amino-[1,2,4]triazolo[1,5-a]pyridines, initially identified from high-throughput screening, to a JAK2 inhibitor with pharmacodynamic activity in a mouse xenograft model is disclosed.
Assuntos
Amitrol (Herbicida)/química , Amitrol (Herbicida)/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Janus Quinase 2/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/uso terapêutico , Triazóis/química , Triazóis/uso terapêutico , Amitrol (Herbicida)/farmacologia , Animais , Antineoplásicos/farmacologia , Cristalografia por Raios X , Humanos , Janus Quinase 2/química , Janus Quinase 2/metabolismo , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.