Peripherally Restricted Slack Activation for Treatment of Itch

Itch (pruritus) is an unpleasant sensation arising from a variety of dermatological, systemic, neuropathic, and psychogenic diseases. Considering that point prevalence of chronic pruritus ranges from 12-20%, while available treatment options are severely limited, there is a high unmet need for novel pharmacotherapeutic strategies to treat pathological itch. In this regard, we present activation of Slack potassium channels as a novel pharmacological treatment strategy. Based on loxapine, an antipsychotic drug reported to activate Slack, we developed a series of compounds with a more favorable selectivity profile, improved pharmacokinetics, and profound on-target efficacy in multiple in vivo models of itch. Moreover, we hypothesized that because Slack is highly enriched in itch-associated sensory neurons of the peripheral nervous system, a Slack activator with restricted blood-brain barrier permeability would be sufficient for exerting antipruritic effects. By this, central nervous system-related adverse effects that potentially arise from the original scaffold of the antipsychotic drug loxapine are avoided. A peripherally restricted small molecule has been developed to underline the therapeutic potential of peripherally restricted Slack activation.