A major objective of this proposal is to design and synthesize long-acting compounds in the morphine class which will bind selectively to mu receptors and act in vivo as selective mu antagonists and will abolish bar-pressing in rats which press for morphine and another group which presses for cocaine. Two compounds which have been synthesized act as specific long-acting (>24h) mu antagonists. In preliminary studies one of them reduced bar-pressing in non-physically dependent rats which were trained to press for morphine and reduced the rate of bar-pressing in rats dependent on cocaine. These compounds and some of their congeners will be studied further in the hope of developing a new modality for treating heroin and cocaine abuse in man. Newly synthesized compounds will first be studied in receptor binding assays. Selectivity and wash-resistance will be the criteria for further evaluation. In vivo studies in mice will furnish data concerning selectivity and duration of action. Compounds of interest will be studied in rats trained to press for morphine and cocaine. Pure morphine antagonists and agonist/antagonists will be examined. Since all compounds selected for further evaluation will have a strong antagonist component, it is anticipated the dependence liability will be minimal. Another major objective of this proposal is to design and synthesize long- acting selective D1 receptor antagonists with the aim of developing agents which will be useful in treating cocaine abuse. The new agents will be tested in dopamine receptor binding assays of the D1 and D2 type to determine selectivity and wash-resistance. Promising compounds will be tested in the cocaine-dependent colony of rats.
