The objective for this research project is the synthesis and preliminary evaluation of several derivatives of narcotic ligands, both potential agonist and antagonist molecules. It is anticipated that such structural variations could lead to the development of a new potent analgesic and/or narcotic antagonist, and that preparation and testing of these compounds will provide greater understanding of the structural requirements involved in the relationships between narcotic agonist and antagonist molecules. Based on the pharmacological activities of naloxone, naltrexone, their 6-methylene analogs, and products formed when these antagonists are treated with methyl lithium, a series of derivatives will be prepared, which are primarily epoxides and aziridines (a few cyclopropanes and episulfides) which resemble these antagonists. Potential agonists, structurally related will be prepared as well. In addition these changes will be incorporated into benzomorphan derivatives. Some potential agonists and antagonists with alkylating functionalities would also be prepared, a few 14-azido compounds will be prepared. All compounds will be screened by determination of ability to inhibit naloxone binding in the rat brain homogenate receptor assay, in the presence and absence of sodium ion. In vivo pharmacological testing for analgesia and antagonism will be arranged at NIDA.