Peptide/benzodiazepine hybrids as ligands of CCKA and CCKB receptors

✍ Scribed by Achim Escherich; Jürgen Lutz; Chantal Escrieut; Daniel Fourmy; A. Stephanie van Neuren; Gerhard Müller; Andrea Schafferhans; Gerhard Klebe; Luis Moroder

• Publisher: Wiley (John Wiley & Sons)
• Year: 2000
• Tongue: English
• Weight: 621 KB
• Volume: 56
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/1097-0282(2000)56:2<55::aid-bip1052>3.0.co;2-m

✦ Synopsis

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 CCK A and CCK B 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 larger series of low molecular weight nonpeptide antagonists to a homology modeling derived CCK B receptor structure revealed a consensus binding mode 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