Replacement of glycine with dicarbonyl and related moieties in analogues of the C-terminal pentapeptide of cholecystokinin: CCK(2) agonists displaying a novel binding mode.
Recent advances in the field of cholecystokinin have indicated the possible occurrence of multiple affinity states of the CCK(2) receptor. Besides, numerous pharmacological experiments performed "in vitro" and "in vivo" support the eventuality of different pharmacological profiles associated to CCK(2) ligands. Indeed, some agonists are essentially anxiogenic and uneffective in memory tests, whereas others are not anxiogenic and appear as able to reinforce memory. The reference compound for the latter profile is the CCK-8 analogue BC 264 (Boc-Tyr(SO(3)H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH(2)). However, although tetrapeptide ligands based on CCK-4 (Trp-Met-Asp-Phe-NH(2)) are known to possess sufficient structural features for CCK(2) recognition, none shares the properties of BC 264. Hence we have developed new short peptidic or pseudo-peptidic derivatives containing the C-terminal tetrapeptide of BC 264. Our results indicate that some compounds characterized by the presence of two carbonyl groups at the N-terminus, as in 2b (HO(2)C-CH(2)-CONH-Trp-(NMe)Nle-Asp-Phe-NH(2)), are likely to show a BC 264-like profile, bind to the CCK(2) receptor in a specific way, and display remarkable affinities (2b: 0.28 nM on guinea-pig cortex membrane preparations). This original binding mode is discussed and further enlightened by NMR and molecular modeling studies.
Bellier
B
B
Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM, UMR 8600 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, 4, Avenue de l'Observatoire, 75270 Paris Cedex 06, France.
Million
M E
ME
DaNascimento
S
S
Meudal
H
H
Kellou
S
S
Maigret
B
B
Garbay
C
C
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism; D002766:Cholecystokinin / Q000737:chemistry*; D006224:Cricetinae; D005998:Glycine / Q000737:chemistry*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D008566:Membranes; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry*; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007295:Inositol Phosphates; D009842:Oligopeptides; D010446:Peptide Fragments; D011949:Receptors, Cholecystokinin; C415152:malonyl-tryptophyl-(N-methyl)norleucyl-aspartyl-phenylalaninamide; D001224:Aspartic Acid; D002766:Cholecystokinin; D005998:Glycine