Enantiomeric - and - heterocyclic N-substituted-normetazocines Synthesis of potent and selective antinociceptives and opioid antagonists through N-substituent modification
May, E.L.; Aceto, M.D.; Bowman, E.R.; Traynor, J.R.; Woods, J.H.; Jacobson, A.E.; Harris, L.S.
Medicinal Chemistry Research 10(3): 178-185
ISSN/ISBN: 1054-2523 Accession: 034846977
A number of diverse N-substituted-N-normetazocine heterocycles ((-)-1R,5R,9R)- and (+)-(1S,5S,9S)-5,9-dimethyl-2'-hydroxy-2-substituted-6,7-benzomorphans) were synthesized and evaluated. Conversion of an antinociceptively inactive alcohol to an ether (-)-1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(2-methoxyethyl)-6,7-benzomorphan ((-)-N-methoxyethylnormetazocine, 4), gave a compound that was 10 to 40 times more potent than morphine as an antinociceptive agent, but did not attenuate morphine withdrawal in monkeys. Other (-)-enantiomers also had potent antinociceptive activity and one, (-)-N-fluoropropylnormetazocine (9), was a potent opioid antagonist.