In response to RFA-DA-05-009, """"""""Strategic Program for Innovative Research on Drug Addiction Pharmacotherapy (SPIRDAP),"""""""" we are pleased to submit this application whose overall goal is developing a pharmacotherapy for use in preventing relapse to cocaine abuse. We have developed a structurally novel, potent, and selective opioid receptor antagonist referred to as JDTic. JDTic reversed antinociception of kappa agonists in mice and squirrel monkeys and antagonized kappa agonist-induced diuresis in rats. It showed activity using subcutaneous, intramuscular, and oral administration routes. To our knowledge, JDTic is the first selective kappa opioid receptor antagonist to show activity using the oral route of administration. Importantly, JDTic prevented stress-induced relapse in a rat cocaine self-administration paradigm and significantly decreased immobility and increased swimming time in the forced-swim test (FST) in rats, the latter suggesting antidepressant activity. Since stress and depression during cocaine abstinence precipitate relapse, and JDTic can attenuate both, it is an ideal development candidate for cocaine relapse pharmacotherapy. This application brings together a group of experienced investigators from four institutions to achieve the goal of developing JDTic as a pharmacotherapy to treat cocaine relapse. Dr. F.I. Carroll (Research Triangle Inst.), Dr. P.M. Beardsley (Virginia Commonwealth Univ.), Dr. T.R. Kosten (Yale Univ.), and Drs. C. Johanson and C.R. Schuster (Wayne State Univ.) have extensive experience in organic and medicinal chemistry, animal behavioral pharmacology, and clinical research, relating to cocaine abuse. The research plan is divided into four projects-one from each organization to reach our goals. Project 1 will synthesize non-GMP JDTic needed to complete preclinical development studies, intermediates needed to prepare the cGMP sample, and analogs needed as back-ups for JDTic. In addition, Project 1 will evaluate back-up compounds for their ability to antagonize kappa agonist-induced diuresis and for antidepressive activity in FST in rats. Project 2 will evaluate compounds from Project 1 in a rat cocaine foot-shocked and cocaine-primed relapse test to prioritize for selection of a back-up compound. Information from all studies will be used to prioritize compounds to be submitted for toxicological evaluation by NIDA and final selection of a backup compound. Projects 3 and 4 will determine if JDTic will be an effective pharmacotherapy for cocaine dependence. The primary purpose of Project 3 is to determine what JDTic doses can be well tolerated in humans with no significant adverse reactions when given acutely. Specifically, Project 3 will access safety, tolerance, and oral pharmacokinetics of isolating single dosages of JDTic in normal humans. Project 4 will ensure no adverse reactions when candidate medication compound and cocaine are combined. Although the primary goal of this research is to determine safety of the test medication when combined with cocaine, obtaining other important information is possible during the study's course. Changes in craving for cocaine and subjective effects of cocaine can also be obtained. Most importantly, the research program will lead to a new chemical entity with potential utility for treating cocaine relapse.
