Chloride extrusion enhancers as novel therapeutics for neurological diseases

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.