The proposed research will be directed toward an understanding of the mechanism of action of narcotic antagonists and to their evolution as practical therapeutic agents in the treatment and prevention of opiate addiction. Both chemical synthetic efforts and biochemical studies are projected. Structure-activity relationships derived from previous successful alterations of naloxone and naltrexone structures suggest that alkyl or alkenyl substitutions at C-6together with modifications of the C-3 phenolic hydroxyl yield potent, pure antagonists. A large additional number of such structures will be prepared for biological evaluation. In addition, changes in the N-allyl and N-cyclopropylmethyl groups show promise of enhancing activity and duration and these will also be carried out. Naltrexone-7,8 H3 will be synthesized to join the already available naloxone-7,8 H3 and morphine- 6H3. These high specific activity labelled substrates offer a new dimension in the study of the disposition and biochemistry of morphine and its antagonists. Such studies are planned in man and in animals with particular emphasis on the effect of antagonists on the fate of morphine and vice versa. The significant biological N-demethlation of morphine can be best examined using a mixture or morphine -N-methyl Cl4 and morphine-6H3. In projected studies we will use double label counting to measure the loss of Cl4 and thus obtain accurate information on the rate and extent of this biotransformation under various conditions. Naloxone-N-ally Cl4 and naloxone-7,8H3 will be similarly used to study the biological N-dealkylation of the antagonist. It is planned to use Cl4 labelled naloxone with H3 labelled morphine and vice versa to locate the site of the opiate receptor. After administration to experimental animals various regions of the central nervous system and other tissues will be examined for their dual isotope content. Isotope ratios indicative of a predominance of the antagonist, when different from adjoining areas, would suggest the presence of the receptor.
NIH ExPorter
NIH ExPorter