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Titolo:
Peptide/benzodiazepine hybrids as ligands of CCKA and CCKB receptors
Autore:
Escherich, A; Lutz, J; Escrieut, C; Fourmy, D; van Neuren, AS; Muller, G; Schafferhans, A; Klebe, G; Moroder, L;
Indirizzi:
Max Planck Inst Biochem, D-82152 Martinsried, Germany Max Planck Inst Biochem Martinsried Germany D-82152 Martinsried, Germany CHU Rangueil, INSERM, U152, F-31054 Toulouse, France CHU Rangueil Toulouse France F-31054 ERM, U152, F-31054 Toulouse, France Bayer AG, Cent Res, ZFLScMB, D-51368 Leverkusen, Germany Bayer AG Leverkusen Germany D-51368 ZFLScMB, D-51368 Leverkusen, Germany Univ Marburg, Dept Pharmaceut Chem, D-35032 Marburg, Germany Univ MarburgMarburg Germany D-35032 ceut Chem, D-35032 Marburg, Germany
Titolo Testata:
BIOPOLYMERS
fascicolo: 2, volume: 56, anno: 2000,
pagine: 55 - 76
SICI:
0006-3525(2000)56:2<55:PHALOC>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
CHOLECYSTOKININ-B RECEPTOR; PENULTIMATE ASPARTIC-ACID; PROTEIN-COUPLED RECEPTORS; 2ND EXTRACELLULAR LOOP; B/GASTRIN RECEPTOR; A RECEPTOR; DIRECT IDENTIFICATION; BINDING-SITES; TRANSMEMBRANE DOMAINS; BIOLOGICAL EVALUATION;
Keywords:
benzodiazepines; peptide/benzodiazepine constructs; synthesis; antagonists; CCKA/CCKB receptors; binding modes;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
89
Recensione:
Indirizzi per estratti:
Indirizzo: Moroder, L Max Planck Inst Biochem, Klopferspitz 18A, D-82152 Martinsried,Germany Max Planck Inst Biochem Klopferspitz 18A Martinsried Germany D-82152
Citazione:
A. Escherich et al., "Peptide/benzodiazepine hybrids as ligands of CCKA and CCKB receptors", BIOPOLYMERS, 56(2), 2000, pp. 55-76

Abstract

The (neuro)hormones gastrin and cholecystokinin (CCK) share a common C-terminal tetrapeptide amide sequence that has been recognized as the message portion while the N-terminal extensions are responsible for the CCKA and CCKB receptor subtype selectivity and avidity. 1,4-Benzodiazepine derivatives are potent and selective antagonists of these receptors, and according to comparative molecular field analysis, the structures of these nonpeptidic compounds could well mimic the message sequence of the peptide agonists at least in terms of spatial array of the aromatic residues. Docking of a largerseries of low molecular weight nonpeptide antagonists to a homology modeling derived CCKB receptor structure revealed a consensus binding made that is further validated by data from site-directed mutagenesis studies of the receptors. Whether this putative binding pocket of the nonpeptide antagonists is identical to that of the message portion of the peptide agonists, or whether it is distinct and spatially separated, or overlapping, but with distinct interaction sites, is still object of debate. Using a 1,4-benzodiazepine core amino-functionalized at the C3 position, related tryptophanyl derivatives were synthesized as mimics of the tetrapeptide and subsequently extended N-terminally with gastrin and CCK address sequences. All hybrid constructs were recognized cis antagonists by the CCKA and CCKB receptors, but their address portions were uncapable of enhancing in significant manner selectivity and avidity. Consequently, the binding of the peptide/benzodiazepine hybrids has to be dictated mainly by the benzodiazepine moiety, which apparently prevents optimal interactions of the address peptides with extracellular receptor subdomains. These findings would strongly support the view of distinct binding sites for the message portion of the peptide agonists and the benzodiazepine-based nonpeptide antagonists. (C) 2001 John Wiley & Sons, Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/10/20 alle ore 15:21:16