Chloride extrusion enhancers as novel therapeutics for neurological diseases

Abstract

The K ⁺-Cl ⁻ cotransporter KCC2 is responsible for maintaining low Cl ⁻ concentration in neurons of the central nervous system (CNS), essential for postsynaptic inhibition through GABA _A and glycine receptors. While 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 ^{1– 9} . Recent reports indicate that enhancing KCC2 activity may be the favoured therapeutic strategy to restore inhibition and normal function in pathological condition involving impaired Cl ⁻ transport ^{10– 12} . We designed an assay for high-throughput screening which led to the identification of KCC2 activators that reduce [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, renormalised 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.