As part of our Laboratory's (LMC) work on the elucidation of the structure and function of neurotransmitter systems in the mammalian central nervous system (CNS) and the molecular mechanism of action of CNS active drugs, a multidisciplinary approach is utilized in our studies which require synthesis of novel agonists, antagonists, imaging agents, affinity ligands and other drugs for particular applications. In one aspect of this work, selective and potent ligands suitable for SPECT (single photon emission computed tomography) scanning were synthesized and evaluated in vitro and in vivo. Thus, 6alpha- and 6beta-iodo-3,14-dihydroxy-17-methyl-4,5alpha- epoxymorphinans were found to be mu-opioid receptor selective, more potent in vitro and in vivo than their 6-hydroxy relatives. Single- crystal analysis showed that the 6alpha- and 6beta-iodine atoms are spatially closely located although the C-ring conformations of these compounds are quite different (twist-boat form vs. chair). These epimeric conformational differences were not reflected in their binding affinities. The C6alpha-iodo compound is more potent than its C6beta-iodo relative in vivo (about 5 times more potent than the latter in suppressing abstinence in the monkey single-dose-suppression (SDS) assay, and 300 times more potent than morphine in that assay) and both may prove to be useful as SPECT ligands. The LMC, NIDDK, incorporates the biological coordination of the work of the Drug Evaluation Committee (DEC) of the College on Problems of Drug Dependence. DEC is involved with methodological research and the testing of drugs with analgesic, stimulant, depressant, and/or hallucinogenic actions, and provides information relating to the physical dependence potential and abuse liability of these drugs to governmental organizations in the U.S. and abroad, the World Health Organization, pharmaceutical industry, and university researchers, as a public service. In that work a compound, N-cyclopropylmethyl-7,8- dihydro-14beta-[3'(methoxycarbony)propenamido] normorphinone was identified with potential as a clinically useful analgesic. It was found to have essentially morphine-like antinociceptive activity. Unlike morphine, however, it did not suppress abstinence in SDS studies and it displayed weak narcotic antagonist properties in a precipitated withdrawal study. It is, thus, unlikely to induce opioid-like physical dependence in man. Another compound, (-)- 5,9alpha-dimethyl-2'-hydroxy-2-(2-hydroxyethyl)-6,7-benzomorphan, was examined, and the biological data indicated that it might have utility as a peripheral analgesic.
NIH ExPorter
NIH ExPorter