Blue Therapeutics I-Corps Application

Project Summary Opioid drugssuch as morphine and oxycodoneare generally the most effective compounds available for treatment of moderate to severe painwhich affects nearlymillion adults in the United StatesIn spite of their analgesic efficacythe use of opioids is limited by an often lethal cluster of side effectsRapid tolerance leads to quickly escalated dosingwhile intolerable withdrawal symptoms build physical dependenceMeanwhiledose dependent euphoria encourages abuse and psychological addiction despite an endgame of lethal opioid induced respiratory arrestThe frequency of clinical paincoupled with a lack of alternative therapeutic optionshas led to a national health crisis centered on prescription opioidsThe CDC now reports that a lethal opioid overdose occurs everyminutes in the U Sand a new overdose patient enters a hospital emergency department every minuteIn responsestate and federal regulatory bodies have recently reduced access to prescription opioidsHoweverthis has also had the effect of forcing many legitimate pain patients toward less effective treatment options in lieu of opioidsoften increasing their pain levels substantiallyThere isthereforea clear and pressing unmet need for safereffective analgesicsTo address this needwe are advancing a novel strategy to develop non addictive analgesics targeting opioid receptor heteromersWe will first develop a diverse set of chemical scaffolds that activate mu kappa opioid receptor heteromersa target shown to produce potent antinociceptionpainrelief in rodentswithout physical dependence or drugseeking behaviorWe will do this by accessing two world class high throughput screening cores at Boston Childrenandapos s Hospital and Harvard Medical School and their combined chemical librariesandgtK compoundsWe will screen andgtof these small molecules to identify activators of mu kappa receptor heteromersstably expressed in cellsNextwe will determine the selectivity of these ligands for this target by generating concentration response curves in cells stably expressing various homomericmukappa and delta individuallyand heteromeric opioid receptorsmu kappamu delta and kappa deltaThe end goal of this SBIR Phase I award is to identify novel scaffolds suitable for subsequent SAR evaluation and potential advancement toward clinical development Project Narrative Opioids like morphine and hydrocodone are arguably the most effective analgesics availablebut their broad clinical use has contributed to a nationwide epidemic of opioid addiction and overdose deaths due to their abuse potential and lethal side effectsTo address the need for effectivenon addictive analgesicswe will generate a series of molecular scaffolds that activate an opioid receptor heteromer shown to produce preclinical antinociception without apparent addictive potentialWe will then perform secondary validation studies using these chemical scaffolds to test them for target selectivitywith the goal of identifying scaffolds suitable for advancement toward clinical development