The major objective of this renewal application is to develop a compound which will block self-administration of cocaine and also heroin by humans addicted to these drugs. The working hypothesis for which we have produced experimental support is that compounds which release dopamine from the nucleus accumbens promote drug-seeking behavior and those which prevent release of this transmitter prevent drug-seeking behavior. Based on our previous studies, we have tentatively concluded that the best approach to achieve our objective is to design and synthesize compounds which are long-acting antagonists by virtue of the fact that they bind covalently to the mu receptor and which have short-term kappa agonist activity. It is known that kappa agonists and mu antagonists inhibit dopamine release in the nucleus accumbens. We will continue to explore other mixed mu antagonists-Kappa agonists in the 14beta-substituted disulfide series (TAMO series) and also prepare some related members in the 6beta-substituted series. This will complete our work in this group of opioid ligands. We have developed a new concept in drug design which is a variant of the concept of Mechanism-based Enzyme Inactivation, which we have termed Mechanism-based Receptor Inactivation. In the morphinan series, we will synthesize some 6beta-substituted-4-aryl-propargyl ketones and the isomeric allenic ketones. The morphinan ring will direct the ligand to a mu receptor which it is hoped will, owing to the presence of basic amino acids, will rearrange the ligand to an allenic ketone which by virtue of its high electrophilicity will bind covalently to the receptor. If this concept does not work the allenic ketones will be used to act as affinity ligands. The binding profiles of each ligand will be determined as well as wash-resistant inhibition of opioid binding. Scatchard analysis of saturation binding experiments will be used as an indication of covalent binding. A radiolabeled ligand will be prepared for covalent binding studies. Antinociception trials will be carried out using the mouse tail-flick test for indications of mu and delta agonist action and the writhing test will be used to assay kappa agonist effects. Studies on opioid antagonism will be run including duration of action. Different routes of administration will be employed, including i.c.v., i.p. and p.o. Selected compounds will be run in self-administration studies in rats and monkeys trained to seek cocaine and heroin/morphine.
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