title: Biological and conformational evaluation of bifunctional compounds for opioid receptor agonists and neurokinin 1 receptor antagonists possessing two penicillamines.
abstract: Neuropathic pain states and tolerance to opioids can result from system changes in the CNS, such as up-regulation of the NK1 receptor and substance P, lead to antiopioid effects in ascending or descending pain-signaling pathways. Bifunctional compounds, possessing both the NK1 antagonist pharmacophore and the opioid agonist pharmacophore with delta-selectivity, could counteract these system changes to have significant analgesic efficacy without undesirable side effects. As a result of the introduction of cyclic and topological constraints with penicillamines, 2 (Tyr-cyclo[d-Pen-Gly-Phe-Pen]-Pro-Leu-Trp-NH-[3',5'-(CF(3))(2)-Bzl]) was found as the best bifunctional compound with effective NK1 antagonist and potent opioid agonist activities, and 1400-fold delta-selectivity over the mu-receptor. The NMR structural analysis of 2 revealed that the relative positioning of the two connected pharmacophores as well as its cyclic and topological constraints might be responsible for its excellent bifunctional activities as well as its significant delta-opioid selectivity. Together with the observed high metabolic stability, 2 could be considered as a valuable research tool and possibly a promising candidate for a novel analgesic drug.
authors.affiliation: Departments of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, USA. takashia_yamamoto@ajinomoto.com
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: 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: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D064729:Neurokinin-1 Receptor Antagonists; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C551939:tyrosyl-cyclo(penicillamine-glycyl-phenylalanyl-penicillamine)-prolyl-leucyl-tryptophyl-NH-(3',5'-(CF3)2-Bzl); D010396:Penicillamine