Potential Long Acting Opiate Antagonists: Preparation, Pharmacological Activity, and Opiate-Receptor Binding of N-Substituted 2′-Hydroxy-5-methyl-9α-propyl-6,7-benzomorphans

A homologous series of TV-substituted 2′-hydroxy-5- methyl-9a-propyl-6,7-benzomorphans (hydrogen to octyl inclusive, allyl, and cyclopropylmethyl) was prepared. In contradistinction to the nor-metazocine, normorphine, and (—)-3-hydroxymorphinan series, the N-pentyl and TV-hexyl derivatives do not have the analgesic potency of the parent TV-methyl compound; instead, they are narcotic antagonists with a long duration of action. All of the N-substituted 9α-propylben-zomorphans, except for methyl, heptyl, and octyl, have antagonist activity. The receptor binding constants of the TV-alkyl compounds are uniformly two- to threefold lower than those of the TV-substituted nor-Narcotic analgesics based on fused ring systems, such as the 6,7-benzomorphans and the more complex morphinans and morphines, have commonly been converted to antagonists by modification of the N-substituent (1, 2) [classically by replacing the N-methyl with allyl (3), cyclopropylmethyl (1), or propyl (1)]. Many antagonists metazocines.