title: Synthesis and binding affinities of cyclic and related linear analogues of CCK8 selective for central receptors.
abstract: To investigate the role of the sulfate group and the influence of cyclization on the biological properties of conformationally constrained CCK8 analogues, three series of compounds were synthesized: Boc-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (1), Boc-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (2), and Boc-Glu-Tyr-(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (3) (series A); Boc-D-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (4), Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (5), Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (6), and Boc-D-Glu-Tyr(SO3H)-Nle-D-Nle-Trp-Asp-Phe-NH2 (7) (series B); and Boc-gamma-D-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (8), Boc-gamma-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (9), and Boc-gamma-D-Glu-Tyr-(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (10) (series C). The selectivity of these peptides was studied by measuring their ability to displace [3H]propionyl-CCK8 from guinea pig brain and pancreatic membranes. All the peptides displayed low affinities (KI values around 10(-6) M) for the pancreatic receptors (A type). In contrast, both sulfated and nonsulfated cyclic analogues displayed high affinities for central-type binding sites (B type), especially compounds belonging to series C [KI(8) = 4.7 nM and KI(9) = 0.56 nM]. In all series the linear analogues had relatively poor affinities (KI approximately 300 nM) for B-type receptors. Compound 9 was the most potent (KI = 0.56 nM) and selective [KI(pancreas)/KI(brain) = 4464] for central-type CCK receptors of guinea pig. The cyclization of the N-terminal region of CCK8 permits one therefore to obtain probes for central receptors, and small changes directed toward the cyclic part modulate the affinity for these receptors.
authors.affiliation: U 266 INSERM, UA 498 CNRS, U.E.R. des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Charpentier
authors.forename: A
authors.initials: A
authors.lastname: Dor
authors.forename: P
authors.initials: P
authors.lastname: Roy
authors.forename: P
authors.initials: P
authors.lastname: England
authors.forename: H
authors.initials: H
authors.lastname: Pham
authors.forename: C
authors.initials: C
authors.lastname: Durieux
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003500:Cyclization; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D010179:Pancreas / Q000378:metabolism; D011487:Protein Conformation; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D012844:Sincalide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011949:Receptors, Cholecystokinin; D012844:Sincalide