title: Novel CCK-B receptor agonists: diketopiperazine analogues derived for CCK4 bioactive conformation.
abstract: Recently, we proposed a CCK-B agonist bioactive conformation characterized by an 'S' shape of the peptidic backbone which was derived from structure-activity relationships and conformational analysis of CCK4 (Trp-Met-Asp-Phe-NH2) analogues. Using this template, we report here the synthesis of cyclic CCK4 analogues which contain, in place of the Trp-Met dipeptide, a diketopiperazine moiety resulting from a cyclization between Nle and N-substituted (D)Trp residues and coupled with a small linker to Asp-Phe-NH2. Some of these compounds displayed good affinities and selectivities for the CCK-B receptor. The results are discussed in terms of size, hydrophobicity and spatial orientation of the side-chains on the diketopiperazine ring. The most potent ligand exhibited potent and full CCK-B receptor agonist properties in promoting the hydrolysis of inositol phosphates (EC50 = 8 nM) in CHO cells, stably transfected with the rat brain CCK-B receptor. This compound was also shown to be a potent selective CCK-B/gastrin receptor agonist since, it increased gastric acid secretion measured in anesthetized rats on i.v. administration. These compounds provide a rigid template for the design of non-peptide CCK-B agonists, by modification of the remaining peptide moiety.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale U266 INSERM -URA D 1500 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Faculté de Pharmacie, Paris, France.
authors.forename: J H
authors.initials: JH
authors.lastname: Weng
authors.forename: A
authors.initials: A
authors.lastname: Bado
authors.forename: C
authors.initials: C
authors.lastname: Garbay
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D002766:Cholecystokinin / Q000737:chemistry*; D054659:Diketopiperazines; D005744:Gastric Acid / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D054659:Diketopiperazines; D007295:Inositol Phosphates; D010879:Piperazines; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin