Cooperative Agreement UH3DA048379

ARYLEPOXAMIDES: A NEW CLASS OF POTENT, SAFER ANALGESICS - THE EXPANSION OF OPIOID PRESCRIBING IN RECENT YEARS TO BETTER TREAT PAIN HAS MARKEDLY INCREASED THEIR USAGE AND AVAILABILITY AND FUELED AN EPIDEMIC OF ABUSE. ESTIMATES OF UP TO 80% OF ADDICTS REPORTED INITIATING THEIR HABIT THROUGH PRESCRIPTIONS DRUGS. DECREASING OPIOID PRESCRIPTIONS WOULD LOWER OPIOID EXPOSURE WITH FEWER PEOPLE RECEIVING THE DRUGS AND LESS DRUG AVAILABLE FOR DIVERSION. WE HAVE IDENTIFIED A NOVEL TARGET IN BRAIN DISTINCT FROM ANY OF THE TRADITIONAL OPIOID RECEPTORS CAPABLE OF MEDIATING POTENT ANALGESIA WITHOUT THE REWARD BEHAVIOR AND SIDE-EFFECTS SEEN WITH TRADITIONAL OPIOIDS. WE HAVE TARGETED THIS SITE WITH A SERIES OF ARYLEPOXAMIDES AND HAVE IDENTIFIED A CLINICAL CANDIDATE (MP1000) AND BACKUP COMPOUND. MP1000 IS A POTENT ANALGESIC IN A RANGE OF THERMAL, INFLAMMATORY AND NEUROPATHIC ANALGESIC ASSAYS. IT FAILS TO SHOW REWARD BEHAVIOR AND DOES NOT PRODUCE RESPIRATORY DEPRESSION AT DOSES 5-FOLD GREATER THAN ITS ANALGESIC ED50. CHRONIC ADMINISTRATION DOES NOT PRODUCE PHYSICAL DEPENDENCE OR WITHDRAWAL WHEN CHALLENGED WITH AN ANTAGONIST. IT SHOWS NO CROSS TOLERANCE TO MORPHINE AND CAN BE CO- ADMINISTERED TO SUBJECTS ALREADY ON OPIOIDS FOR PAIN TO LOWER THEIR OPIOID USAGE (I.E. 'OPIOID SPARING), FACILITATING THE EVENTUAL DISCONTINUATION OF THE OPIOID. PRELIMINARY SAFETY AND TOXICOLOGY STUDIES ARE ENCOURAGING, AND, BASED UPON THESE RESULTS WE ARE PROPOSING TO CARRY OUT IND- ENABLING STUDIES AND A PHASE 1 CLINICAL TRIAL.