Replacement of the peptide-backbone amides connecting Tyr-Gly and Gly-Gly in leucine-enkephalin with ketomethylene groups: synthesis and biological activity

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Abstract
A peptide analogue of Leu-enkephalin was synthesized in which the amide linkages between Tyr-Gly and Gly-Gly were replaced by ketomethylene groups. The resulting analog, 12 had 1/4000th and 1/2400th the opiate receptor binding activity of Leu-enkephalin when (3H)[D-Ala2,D-Leu5]enkephalin and (3H)naloxone, respectively, were used as 3H-ligands. When tested for analgesia in mice by the tail-flick assay, 12 produced analgesia in 50% of the mice tested at a dose of 24.3 .mu.g/mouse (icv [intracerebroventricular]), while the ED50 of Leu-enkephalin is 240 .mu.g/mouse (icv). At a dose of 40 .mu.g/mouse (icv) or higher, 12 caused convulsions in a dose-dependent manner. No analgesia was observed after i.v. administration of 240 .mu.g/mouse of 12.