Discovering GIRK Channel Direct Activator as a Novel Chronic Insomnia Therapeutic

PROJECT SUMMARY Millions of Americans suffer from sleep disturbances among which insomnia is the most commonInsomnia is often poorly treated with current pharmacotherapies and we propose to develop a new sleep promoting therapeutic based on selective and direct activation of the G protein gated inward rectifier KchannelsGIRKGIRK channels in the brainpredominantly GIRKplay a key role in controlling neuronal excitabilityActivation of the GIRK channels by neurotransmitters and neuropeptidessuch as GABA and galaninpromote sleepThe link between GIRK function and animal NREM sleep was based on both preclinical and clinical evidence that shows GIRK activation by GABAB agonistse gbaclofen andhydroxybutyric acidGHBpreferentially promote non rapid eye movementNREMsleepleading to enhanced maintenance of sleepIn our collaborative project led by DrWeaverwe discovered the GIRK channel biologic probe MLwhich selectively activates recombinant human GIRK channels with a half maximal effective concentrationECofnM for neuronal GIRKwith afold selectivity over cardiac GIRKchannelsRecentlywe eliminated the concern of MLon cardiac safety using the cardiac ion channels panel consisting of hERGhCavand hNavchannelsICand andgtMrespectivelyMLhad little effects on spontaneous action potential firing in hiPSC derived cardiomyocytes uptoMPharmacokineticPKstudies indicated that MLhad acceptable brain penetrationPharmacodynamicPDstudies confirmed that MLcan activate native neuronal GIRK channels in hypocretin orexin neurons and hippocampal neuronsFurthermore MLmg kgi pinhibited spontaneous activity and prolonged inactive sleep state in mice using our validated noninvasive wake sleep monitoring systemSmartCageTMA study employing electroencephalogram and electromyogramEEG EMGrecordings revealed that MLsignificantly enhanced NREM sleep in mice in a dose dependent mannerWe now propose to use MLas a starting point to develop a new therapeutic for insomnia because it is amenable to chemical modification to generate druggable analogs and it has no intellectual property roadblocksWe will achieve our goal through the accomplishment of two Specific AimsAimLead modificationExplore the structure activity relationshipSARofnew synthetic analogs derived from MLand identify the topmodified leads with increased potency and selectivityAimTherapeutic lead discovery through in vitro and in vivo PK studiesWe will determine the in vivo PK profiles of the topnew leads and test the best lead in a pilot sleep study in rats using EEG EMGSuccess in the Phase I project will demonstrate feasibility of discovering a druggable GIRKchannel direct activatorIn a Phase II projectwe will focus on lead optimization to discover a safe therapeutic candidate with desirable PK PD profile for the IND enabling studiesand ultimately for the treatment of chronic insomniaPROJECT NARRATIVE Millions of Americans suffer from sleep disordersespecially insomniawhich is often poorly treatedChronic insomnia can lead to reduced quality of life and increased risks for cardiovascular diseases and metal disordersWe propose to develop a novel drug that can promote sleep and improve the maintenance of sleep in order to enhance sleep quality