title: Improving metabolic stability by glycosylation: bifunctional peptide derivatives that are opioid receptor agonists and neurokinin 1 receptor antagonists.
abstract: In order to obtain a metabolically more stable analgesic peptide derivative, O-beta-glycosylated serine (Ser(Glc)) was introduced into TY027 (Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3',5'-Bzl(CF(3))(2)) which was a previously reported bifunctional compound with delta/micro opioid agonist and neurokinin-1 receptor antagonist activities and with a half-life of 4.8 h in rat plasma. Incorporation of Ser(Glc) into various positions of TY027 gave analogues with variable bioactivities. Analogue 6 (Tyr-d-Ala-Gly-Phe-Nle-Pro-Leu-Ser(Glc)-Trp-NH-3',5'-Bzl(CF(3))(2)) was found to have effective bifunctional activities with a well-defined conformation with two beta-turns based on the NMR conformational analysis in the presence of DPC micelles. In addition, 6 showed significant improvement in its metabolic stability (70 + or - 9% of 6 was intact after 24 h incubation in rat plasma). This improved metabolic stability, along with its effective and delta selective bifunctional activities, suggests that 6 could be an interesting research tool and possibly a promising candidate as a novel analgesic drug.
authors.affiliation: Department of Chemistry, University of Arizona, 1306 E. University Boulevard, Tucson, AZ 85721, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Padma
authors.initials: P
authors.lastname: Nair
authors.forename: Neil E
authors.initials: NE
authors.lastname: Jacobsen
authors.forename: Josef
authors.initials: J
authors.lastname: Vagner
authors.forename: Vinod
authors.initials: V
authors.lastname: Kulkarni
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.forename: Shou-Wu
authors.initials: SW
authors.lastname: Ma
authors.forename: Edita
authors.initials: E
authors.lastname: Navratilova
authors.forename: Henry I
authors.initials: HI
authors.lastname: Yamamura
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000700:Analgesics / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006031:Glycosylation; D006168:Guinea Pigs; D006860:Hydrogen Bonding; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000700:Analgesics; D008024:Ligands; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides; D018040:Receptors, Neurokinin-1; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C550441:Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Ser(Glc)-Trp-NH-3',5'-Bzl(CF3)2