Project Grant R44DA053846

DEVELOPMENT OF CP-ANALOGS AS NOVEL TREATMENTS FOR OPIOID USE DISORDER. - ABSTRACT OPIOID USE DISORDER (OUD) IS A CHRONIC DISORDER CHARACTERIZED BY THE REPEATED, COMPULSIVE USE OF OPIOID DRUGS WITH A DETRIMENTAL IMPACT TO ONE'S PHYSICAL, SOCIAL, AND PSYCHOLOGICAL WELLBEING. THE USE OF PRESCRIPTION OPIATES IS OFTEN NECESSARY TO CONTROL MODERATE TO SEVERE LEVELS OF PAIN. HOWEVER, ABOUT 10% OF PATIENTS PRESCRIBED AN OPIATE FOR A MEDICAL CONDITION ARE AT RISK FOR DEVELOPING OUD. OPIATE USE DISORDER IS A GLOBAL PROBLEM BUT IS AT CRISIS LEVELS IN THE U.S WITH SIGNIFICANT MORTALITY. IT IS ESTIMATED IN THIS COUNTRY THAT ABOUT ~11M MISUSE OPIOIDS, ~2M PEOPLE HAVE OUD AND CLOSE TO 50K DIED FROM OPIOID RELATED OVERDOSES. AT SPARIAN, WE HAVE ASSEMBLED A COMPREHENSIVE TEAM OF ACCOMPLISHED SCIENTISTS, KEY CLINICAL OPINION LEADERS, AND PHARMACEUTICAL INDUSTRY EXPERTS ACROSS CRITICAL DISCIPLINES INCLUDING TRANSLATIONAL RESEARCH, MEDICINAL CHEMISTRY, CMC, TOXICOLOGY AND CLINICAL TRIALS IN AN EFFORT TO DEVELOP AN ORAL, POTENT, AND SELECTIVE SMALL MOLECULES FOR THE TREATMENT OF OUD. MITRAGYNA SPECIOSA, A PLANT COMMONLY KNOWN AS KRATOM, IS COMMONLY USED IN THE US AS A SELF-REMIDY TO TREAT OPIATE WITHDRAWAL AND OUD. WE HAVE IDENTIFIED AND SYNTHESIZED A DISTINCT NEW CHEMICAL ENTITY BASED ON KRATOM NAMED 9-METHOXY CORYNANTHEIDINE PSEUDOINDOXYL (9CP). 9CP HAS A DIFFERENT RECEPTOR BINDING PROFILE AND DIFFERENT PHARMACOLOGY THAN MITRAGYNINE. 9CP IS BOTH A POTENT A MOR AGONIST AND DELTA ANTAGONIST. IN ACUTE DOSING STUDIES IT ATTENUATES PRECIPITATED WITHDRAWAL, IT IS NOT REWARDING, DOES NOT CAUSE PHYSICAL DEPENDENCE, AND HAS LIMITED RESPIRATORY DEPRESSION AND TOLERANCE. OUR FAST TRACT PROPOSAL AIMS TO TAKE AN INNOVATIVE PHARMACOLOGICAL APPROACH TO DEVELOP ORALLY ACTIVE, HIGHLY POTENT AND SELECTIVE 9CP ANALOGS, DEVOID OF UNWANTED SIDE EFFECTS, FOR THE TREATMENT OF OUD WITH A BETTER PHARMACOTHERAPEUTIC PROFILE THAN EITHER METHADONE OR BUPRENORPHINE. IT IS ORGANIZED INTO TWO COORDINATED PHASES THAT EMPLOY A SUCCINCT EXPERIMENTAL PLAN AND A FOCUSED DRUG DEVELOPMENT APPROACH. IN PHASE 1, WE WILL USE AN IN VITRO AND IN VIVO SCREENING PARADIGM TO SELECT ONE LEAD MOLECULE AND 5-8 BACKUP MOLECULES WITH SUITABLE DRUG-LIKE PROPERTIES. IN PHASE 2, WE WILL PROGRESS THE SELECTED LEAD AND CONFIRM OUR CHOICE THOUGH EXPLORATORY SAFETY AND TOXICOLOGY STUDIES, WHILE ALSO CHARACTERIZING OUR BACKUP COMPOUNDS TO BETTER UNDERSTAND OUR TEMPLATE MITIGATING RISK. IN SUMMARY, WE PROPOSE A NOVEL STRATEGY TO DEVELOP A NEW CLASS OF AGENTS WITH POTENTIAL TO PROVIDE BETTER THERAPY FOR OUD.