title: Synthesis and structure-activity relationships of an orally available and long-acting analgesic peptide, N(alpha)-amidino-Tyr-D-Arg-Phe-MebetaAla-OH (ADAMB).
abstract: A novel dermorphin tetrapeptide N(alpha)-amidino-Tyr-D-Arg-Phe-MebetaAla-OH (ADAMB) was designed based on the structures of several dermorphin tetrapeptide analogues, including N(alpha)-amidino-Tyr-D-Arg-Phe-Gly-OH (ADA-DER), H-Tyr-D-Arg-Phe-betaAla-OH (TAPA), and H-Tyr-D-Arg-Phe-Sar-OH (DAS-DER). These parent compounds were known to show a weak oral analgesic activity in animals and/or to possess a different mechanism of analgesia from other mu-opioid peptides. Six analogues of ADAMB were also synthesized to investigate the effect on potency of N-terminal amidination and N-methyl-beta-alanine (MebetaAla) substitution at position 4. Compounds were assessed using the tail pressure test in mice after subcutaneous and oral administration. Among the peptides tested, ADAMB showed the strongest oral antinociceptive activity, with an ED(50) of 5.8 vs 22.2 mg/kg for morphine, as well as a 38-fold stronger activity after subcutaneous administration. ADAMB also showed long-lasting antinociceptive activity, with 50% of the maximum effect persisting in the tail pressure test at 10 h after oral administration (10 mg/kg). In contrast, orally administered morphine (80 mg/kg) showed a rapid decrease of activity in the same test and its antinociceptive effect disappeared within 4 h. When the antinociceptive effect of ADAMB was compared with that of analogues possessing betaAla(4) (1) or Sar(4) (2), as well as analogues with N-substitution (3-6), it was found that both the N(alpha)-amidino substitution and the MebetaAla(4) were synergistically involved in creating ADAMB's exceptionally high antinociceptive activity.
authors.affiliation: Research Institute, Daiichi Fine Chemical Co. Ltd., 530 Chokeiji, Takaoka, Toyama 933-8511, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Tetsuhisa
authors.initials: T
authors.lastname: Miyamae
authors.forename: Kimie
authors.initials: K
authors.lastname: Murayama
authors.forename: Kaori
authors.initials: K
authors.lastname: Okuyama
authors.forename: Toru
authors.initials: T
authors.lastname: Okayama
authors.forename: Masaki
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakurada
authors.forename: Tadanori
authors.initials: T
authors.lastname: Morikawa
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D002531:Cerebellum / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010147:Pain Measurement; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013329:Structure-Activity Relationship; D013623:Tail
chemical_list: D000700:Analgesics; C468794:N(alpha)-amidinotyrosyl-arginyl-phenylalanyl-methyl-beta-alanine; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009020:Morphine