Synthesis and Binding Affinities of Cyclic and Related Linear Analogues of CCK8 Selective for Central Receptors

Article abstract of DOI:10.1021/jm00126a007

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: (1), (2), and Boc-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (3) (series A); (4), (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-Nle-Asp-Phe-NH2 (7) (series B); and (8), (9),and Boc-γ-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 (K_I 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 I(8) = 4.7 nM and K_I(9) = 0.56 nM>.In all series the linear analogues had relatively poor affinities (K_I ca. 300 nM) for B-type receptors.Compound 9 was the most potent (K_I = 0.56 nM) and selective I(pancreas)/K_I(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.