RESUMO
The K(+)-Cl(-) cotransporter KCC2 is responsible for maintaining low Cl(-) concentration in neurons of the central nervous system (CNS), which is essential for postsynaptic inhibition through GABA(A) and glycine receptors. Although no CNS disorders have been associated with KCC2 mutations, loss of activity of this transporter has emerged as a key mechanism underlying several neurological and psychiatric disorders, including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia and chronic pain. Recent reports indicate that enhancing KCC2 activity may be the favored therapeutic strategy to restore inhibition and normal function in pathological conditions involving impaired Cl(-) transport. We designed an assay for high-throughput screening that led to the identification of KCC2 activators that reduce intracellular chloride concentration ([Cl(-)]i). Optimization of a first-in-class arylmethylidine family of compounds resulted in a KCC2-selective analog (CLP257) that lowers [Cl(-)]i. CLP257 restored impaired Cl(-) transport in neurons with diminished KCC2 activity. The compound rescued KCC2 plasma membrane expression, renormalized stimulus-evoked responses in spinal nociceptive pathways sensitized after nerve injury and alleviated hypersensitivity in a rat model of neuropathic pain. Oral efficacy for analgesia equivalent to that of pregabalin but without motor impairment was achievable with a CLP257 prodrug. These results validate KCC2 as a druggable target for CNS diseases.
Assuntos
Analgésicos/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Simportadores/agonistas , Tiazolidinas/uso terapêutico , Analgésicos/química , Animais , Células CHO , Cloretos/metabolismo , Cricetinae , Cricetulus , Modelos Animais de Doenças , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Líquido Intracelular/metabolismo , Transporte de Íons/efeitos dos fármacos , Masculino , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Ratos , Ratos Sprague-Dawley , Tiazolidinas/química , Cotransportadores de K e Cl-RESUMO
A remarkable stereoselective reaction of methylglyoxal with 2-aminopyridine, the nucleic base adenine and adenine nucleosides leads in good yield to heterocycles of a new family in water under mild conditions and should be of interest in the understanding of the biological effects of methylglyoxal which is toxic, mutagenic and involved in diabetic complications.
