Novel treatment of posttraumatic stress disorder

Project Summary The present applicationNovel Treatment for Posttraumatic Stress Disorderaddresses the critical need for more efficacious treatments for posttraumatic stress disorderPTSDThe excitatory neurotransmitterglutamateactivates a key neural signaling cascade upon a trauma experienceIn this activationglutamate binds to and activates the NMDA receptora glutamate receptor subtypeBinding and activation triggers the formation of a complex at the receptor and leads to activation of the enzyme neuronal nitric oxide synthasenNOSand a concomitant increase in the production of the signaling molecule nitric oxideNOThese events trigger aberrant synaptic plasticity that is implicated in the initiation and maintenance of PTSDPostsynaptic density proteinPSDtargets nNOS to the NMDA receptor facilitating the formation of this signaling complexPSDis thereforerequired for NMDA receptor activation of nNOSLaiAnagin co founder and principal investigator for this projectfirst showed that the small moleculeICdisrupts the functional protein protein interaction between nNOS and PSDin vitro and attenuates NMDA receptor dependent hyperalgesia in vivoAnaginan Indiana based small business and its preclinical team at Indiana Universityled by DrShekharco founder of Anaginhas demonstrated that ICand a related analogZLblock the long term encoding of conditioned fear even after a fear conditioning session has occurredi eposttraumaUnlike NMDA receptor antagoniststhese protein interaction inhibitors are efficacious in suppressing PTSD like symptoms in a well established preclinical model without producing motor or memory impairmentThusdisruption of signal compartmentalization represents an innovative approach to develop novel treatments for anxiety disorders with fewer side effectsIn Anagin s successful SBIR Phase I studiesthe team established positive structural activity relationship and demonstrated oral efficacy of its first generation lead and identified a promising new chemical seriesThe goal of this Phase II SBIR is to deliver an orally available drug candidate and initiate IND enabling studies delineated through two specific aimsAimPerform lead optimization studies to select a Drug Development CandidateAimValidate the Drug Development Candidate in IND enabling studiesA traditional drug medicinal chemistry approach will be used to design and develop novel analogs with improved pharmacokinetic properties and potency compared to the parent compoundsAnagin anticipates completion of initial IND enabling studies at the end of the grant periodThe development of effective pharmacotherapies with novel chemical structures that possess limited side effect profiles is expected to drive down escalating health care costs and alleviate unnecessary suffering in PTSD patientsThe ultimate goal is an FDA IND submission of a drug candidate for Phase I clinical trials in PTSD or anxiety disorders