During the last few years, we have been conducting research directed toward the development of selective kappa opioid receptor antagonists. The major overall goal was to discover and develop pharmacotherapies to treat cocaine relapse. These studies have led to the discovery of the highly potent and selective kappa opioid antagonist JDTic. In the [35S]GTPgammaS in vitro functional assay, JDTic showed no agonist activity at levels of 10 mu M, possessed a Ke of 0.01 nM for the kappa receptor, and is 341- and 7930- fold selective for the kappa receptor relative to the mu and delta receptors. JDTic reversed antinociception of kappa agonists in mice and squirrel monkeys and antagonized kappa agonist-induced diuresis in rats. It showed activity using subcutaneous (s.c.), intramuscular (i.m.), and oral (p.o.) routes of administration. To our knowledge, JDTic is the first selective kappa opioid receptor antagonist to show activity using the oral route of administration. Importantly, JDTic selectively 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, a test that suggests antidepressant activity. Stress and depresssion are two states during cocaine abstinence that are known to precipitate relapse. The fact that preliminary studies have shown that JDTic can attenuate both stress and depression makes it an ideal candidate for development as a pharmacotherapy for cocaine relapse. Its merit as a potential pharmacotherapy is further supported by its highly favorable toxicity profile in several in vitro tests, its low toxicity in mice and rats, and its opioid receptor selectivity in a 61 assay NovaScreen. (Details will be provided in the Preliminary Studies.) Studies proposed in this response to RFA-DA-05-009, """"""""Strategic Program for Innovative Research on Drug Addiction Pharmacotherapy (SPIRDAP),"""""""" involve completion of preclinical development followed by Phase I clinical trials in normal human volunteers and then in cocaine-dependent volunteers with the potent and selective kappa opioid receptor antagonist JDTic.
The aims of Project 1 are: (1) to provide JDTic needed to complete the preclinical studies, which will largely be carried out through support from NIDA;(2) to provide support in the form of intermediates needed to prepare the cGMP sample that will be used in Projects 3 and 4 after formulation;(3) to develop a back-up compound by synthesizing and evaluating JDTic analogs for their ability to antagonize kappa agonist-induced diuresis, thus, establishing a kappa antagonist activity profile for selecting compounds for testing in Project 2. Findings in Project 2 will inform prioritization of compounds to be evaluated for antidepressive activity in Project 1. Information from all the studies will be used for prioritization of compounds to be submitted for toxicological evaluation by NIDA and final selection of a back-up compound.
