Project Grant R41DA056334

USING IN-VIVO REAL-TIME BIOSENSOR TO EVALUATE PRODRUGS DESIGNED TO PROLONG THERAPEUTIC EFFECTS FOR SMOKING CESSATION. - ABSTRACT DEVELOPING DRUGS THAT TARGET THE CENTRAL NERVOUS SYSTEM (CNS) IS HAMPERED BY AN INABILITY TO PERFORM DIRECT IN VIVO PRECLINICAL MEASUREMENTS. HERE, WE PROPOSE TO IDENTIFY AN OPTIMAL SMOKING CESSATION DRUG CANDIDATE BY MONITORING HOW OUR NEWLY SYNTHESIZED PRODRUGS ALTER REAL-TIME BRAIN DOPAMINE RESPONSES TO NICOTINE. VARENICLINE (CHANTIX) IS THE LEADING FDA-APPROVED ORAL MEDICATION FOR SMOKING CESSATION. HOWEVER, ONLY 22% OF PATIENTS MAINTAIN ABSTINENCE FOR 52 WEEKS FOLLOWING VARENICLINE TREATMENT1 AND 67% OF PATIENTS STOP TREATMENT PREMATURELY2, SUGGESTING THAT THERAPIES WITH BETTER PATIENT COMPLIANCE ARE NEEDED. TO ADDRESS THIS NEED, WE RECENTLY DEVELOPED EXTENDED-RELEASE PRODRUGS THAT ARE DESIGNED TO IMPROVE THE PHARMACOKINETIC PROPERTIES OF VARENICLINE. VARENICLINE REDUCES NICOTINE CRAVING AND USE BY DUAL ACTION: FIRST PROVIDING A TRANSIENT INCREASE IN DOPAMINE LEVELS AND SUBSEQUENTLY BY BLOCKING THE DOPAMINE RESPONSE TO NICOTINE3-5. THESE CHANGES AIM TO STABILIZE DOPAMINE SIGNALING IN THE BRAIN TO ACHIEVE TWO GOALS: (1) REDUCE THE SIDE EFFECTS OF TRANSIENTLY DOPAMINE INCREASES AND (2) PROLONG THE DURATION WITH WHICH THE DRUG REDUCES THE REWARD VALUE OF NICOTINE. IN THIS PHASE I GRANT, WE WILL USE AN IN VIVO DOPAMINE BIOSENSOR TO EVALUATE REAL-TIME DOPAMINE LEVELS IN THE STRIATUM (A REWARD CENTER IN THE BRAIN) FOLLOWING ADMINISTRATION OF OUR NOVEL PRODRUGS. WE WILL ESTABLISH AN IN VIVO RELATIONSHIP BETWEEN BRAIN EFFICACY (AS DEFINED BY DOPAMINE RELEASE) AND DRUG LEVELS IN CIRCULATION. THESE STUDIES WILL ALLOW US TO SCREEN FOR PRODRUGS THAT HAVE OPTIMAL EFFICACY FOR ALTERING BOTH THE LEVEL AND DURATION OF DOPAMINE RESPONSE, WHICH WE USE AS A BIOMARKER FOR PREDICTING EFFICACY FOR SMOKING CESSATION. THE PRIMARY HYPOTHESIS OF THIS PHASE I GRANT IS THAT A PRODRUG THAT STABILIZES THE INITIAL DOPAMINE RELEASE IN THE STRIATUM WHILE ALSO MORE EFFICIENTLY BLOCKING SUBSEQUENT DOPAMINE RESPONSES TO NICOTINE WILL BE MORE EFFECTIVE THAN VARENICLINE AT DECREASING IV SELF-ADMINISTRATION OF NICOTINE. WE WILL TEST THIS HYPOTHESIS BY: 1) ESTABLISHING PHARMACOKINETICS FOR EACH PRODRUG RELATIVE TO VARENICLINE; 2) MEASURING STRIATAL DOPAMINE LEVELS USING REAL-TIME IN VIVO BIOSENSORS TO DETERMINE HOW DIFFERENT EXPOSURE CURVES AFFECT DOPAMINE RESPONSE; AND 3) ASSESSING BEHAVIORAL CHANGES IN RESPONSE TO THE PRODRUGS USING A WELL-ESTABLISHED NICOTINE ADDICTION MODEL. OUR INITIAL PILOT DATA DEMONSTRATE THAT, IN COMPARISON TO VARENICLINE, OUR PRODRUGS FAVORABLY ALTER THE DOPAMINE RELEASE PROFILE IN THE STRIATUM. THUS, OUR PRODRUG APPROACH CHANGES THE PHYSIOLOGICAL FUNCTION OF THE REWARD SYSTEM AND MAY BE A BETTER DRUG FOR CLINICAL USE. IMPORTANTLY, THE CORE TECHNOLOGY USED IN THIS GRANT TO DEVELOP IMPROVED SMOKING CESSATION DRUGS CAN BE UTILIZED MORE BROADLY AS A GENERAL PHARMACODYNAMIC ASSAY FOR CNS DRUG DEVELOPMENT. THEREFORE, THIS RESEARCH WILL PROVIDE A PLATFORM FOR DRUG DISCOVERY USING IN VIVO REAL- TIME METHODOLOGIES. SPACERX HAS EXTENSIVE EXPERIENCE MAKING VARENICLINE ANALOGS AND PRODRUGS, AND REAL- TIME BIOSENSING AND MEASURING NEURAL ACTIVITY DYNAMICS IS A CORE TECHNOLOGY OF THE BETLEY LABORATORY, MAKING OUR TEAM IDEALLY SUITED TO TEST OUR HYPOTHESIS TO SUCCESSFULLY DEVELOP NOVEL SMOKING CESSATION DRUGS.