Replacement of the peptide-backbone amides connecting Tyr-Gly and Gly-Gly in leucine-enkephalin with ketomethylene groups: synthesis and biological activity.
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 analogue, 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 tritiated 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 micrograms/mouse (icv), while the ED50 of Leu-enkephalin is 240 micrograms/mouse (icv). At a dose of 40 micrograms/mouse (icv) or higher, 12 caused convulsions in a dose-dependent manner. No analgesia was observed after intravenous (iv) administration of 240 micrograms/mouse of 12.
D000698:Analgesia; D000818:Animals; D001681:Biological Assay; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000378:metabolism; D005998:Glycine; D051379:Mice; D011957:Receptors, Opioid / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D013329:Structure-Activity Relationship; D014443:Tyrosine
D011957:Receptors, Opioid; D014443:Tyrosine; D004743:Enkephalin, Leucine; D005998:Glycine