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Titolo:
Further studies on nociceptin-related peptides: Discovery of a new chemical template with antagonist activity on the nociceptin receptor
Autore:
Guerrini, R; Calo, G; Bigoni, R; Rizzi, A; Varani, K; Toth, G; Gessi, S; Hashiba, E; Hashimoto, Y; Lambert, DG; Borea, PA; Tomatis, R; Salvadori, S; Regoli, D;
Indirizzi:
Univ Ferrara, Dept Expt & Clin Med, Pharmacol Sect, I-44100 Ferrara, ItalyUniv Ferrara Ferrara Italy I-44100 harmacol Sect, I-44100 Ferrara, Italy Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy Univ Ferrara Ferrara Italy I-44100 harmaceut Sci, I-44100 Ferrara, Italy Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy Univ Ferrara Ferrara Italy I-44100 tr Biotechnol, I-44100 Ferrara, Italy Biol Res Ctr, Inst Biochem, Isotope Lab, H-6701 Szeged, Hungary Biol Res Ctr Szeged Hungary H-6701 , Isotope Lab, H-6701 Szeged, Hungary Univ Leicester, Leicester Royal Infirm, Dept Anaesthesia, Leicester LE1 5WW, Leics, England Univ Leicester Leicester Leics England LE1 5WW er LE1 5WW, Leics, England
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 15, volume: 43, anno: 2000,
pagine: 2805 - 2813
SICI:
0022-2623(20000727)43:15<2805:FSONPD>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
ORPHANIN-FQ NOCICEPTIN; MOUSE VAS-DEFERENS; RAT SPINAL-CORD; OPIOID RECEPTOR; ORL1 RECEPTOR; IN-VITRO; PHARMACOLOGICAL CHARACTERIZATION; ANESTHETIZED RATS; RELEASE; INHIBITION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
65
Recensione:
Indirizzi per estratti:
Indirizzo: Regoli, D Univ Ferrara, Dept Expt & Clin Med, Pharmacol Sect, Via Fossato Mortara 17, I-44100 Ferrara, Italy Univ Ferrara Via Fossato Mortara 17 Ferrara Italy I-44100 Italy
Citazione:
R. Guerrini et al., "Further studies on nociceptin-related peptides: Discovery of a new chemical template with antagonist activity on the nociceptin receptor", J MED CHEM, 43(15), 2000, pp. 2805-2813

Abstract

Three series of nociceptin (NC)-related peptides were synthesized and their abilities (i) to bind to the NC sites expressed in mouse forebrain membranes, (ii) to inhibit the electrically evoked contraction of the mouse vas deferens, and (iii) to inhibit forskolin-stimulated cAMP accumulation in Chinese hamster ovary cells expressing the human recombinant NC receptor (CHONCR) were investigated. The compounds of the first series (a series) have anordinary Xaa(1)-Gly(2) bond, those of the second series (b series) have a Xaa(1)Psi(CH2-NH)Gly(2) pseudopeptide bond, and those of the third series (c series) have a peptoid (Nxaa(1)-Gly(2)) structure. The affinity values measured in the binding assay and in the two functional assays with the compounds of the three series showed high levels of correlation. Thus, (I) the compounds of the a series in which Phe(1) was substituted with Tyr, Cha, or Leu acted as potent NC receptor agonists; (II) the b series compounds behaved as NC receptor antagonists in the mouse vas deferens and as full agonists in CHONCR cells with different potencies depending on the first amino acid residue, [Phe(1)Psi(CH2-NH)Gly(2)]NC(1-17)NH2 and [Phe(1)Psi(CH2-NH)Gly(2)]NC(1-13)NH2 being the most potent compounds; (III) the compounds of the third series were all inactive both as agonists and as antagonists with the exception of [Nphe(1)]NC(1-17)NH2 and [Nphe(1)]NC(1-13)NH2, which behaved as NC receptor antagonists both in the isolated tissue and in CHONCR cells (pK(B) 6.1-6.4). In conclusion, this study demonstrates that chemical requirements for NC receptor agonists are different from those of antagonists. Moreover, modifications of the steric orientation of the aromatic residue Phe(1) in the NC sequence as obtained with the pseudopeptide bond between Phe(1) and Gly(2) or with the displacement of the benzyl side chain by one atom, as in Nphe(1), lead respectively to reduction or elimination of efficacy. Indeed, in contrast to [Phe(1)Psi(CH2-NH)Gly(2)]NC(1-13)NH2 which has beenreported to exhibit agonist activity in several assays involving either central or recombinant NC receptors, [Nphe(1)]NC(1-13)NH2 antagonizes the effect of NC at human recombinant NC receptors and in the mouse tail withdrawal assay.

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Documento generato il 04/04/20 alle ore 12:07:49