117903-30-7Relevant academic research and scientific papers
CCK-B agonist or antagonist activities of structurally hindered and peptidase-resistant Boc-CCK4 derivatives
Corringer,Weng,Ducos,Durieux,Boudeau,Bohme,Roques
, p. 166 - 172 (2007/10/02)
Replacement of Met31 by (N-Me)Nle in CCK8 or CCK4 has been shown to improve the affinity and selectivity for CCK-B receptors. In order to obtain molecules with enhanced bioavailability, two novel series of protected tetrapeptides of the general formula Boc-Trp30-X-Asp-Y33 have been developed. Introduction of (N-Me)Nle and the bulky, aromatic naphthylalaninamide (Nal-NH2) in positions X and Y, respectively, does not greatly modify the affinity for guinea pig brain CCK-B receptors. In contrast, incorporation of hindering N-methyl amino acids such as (N-Me)Phe, (N-Me)Phg, or (N-Me)Chg, but not their non-methylated counterparts, in position X induced a large decrease in affinity for the CCK-B binding sites. Among the various peptides synthesized, Boc-[(N-Me)Nle31,1Nal- NH233]CCK4 (2) (K(I) = 2.8 nM), Boc-[Phg31,1Nal-NH233]CCK4 (15) (K(I) = 14 nM), and Boc-[Phg31,1Nal-N(CH3)233]CCK4 (17) (K(I) = 39 nM) displayed good affinities for brain CCK-B receptors and had good selectivity ratios. These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases. Interestingly, whereas compounds 2 and 15 proved to be full agonists for rat hippocampal CCK-B receptors when measured in an electrophysiological assay, compound 17 behaved as a potent antagonist in the same test and displayed a good affinity in rat brain K(I)(CCK-B) = 51 nM as compared to the Merck antagonist L365,260, K(I)(CCK-B) = 12 nM. This illustrates a simple means to obtain CCK-B antagonists and suggests that the free, CONH2 group plays a critical role in the recognition of the agonist state of brain CCK-B receptors.
Synthesis and Binding Affinities of Cyclic and Related Linear Analogues of CCK8 Selective for Central Receptors
Charpentier, Bruno,Dor, Adeline,Roy, Pierre,England, Patrick,Pham, Hung,et al.
, p. 1184 - 1190 (2007/10/02)
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 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 I(8) = 4.7 nM and KI(9) = 0.56 nM>.In all series the linear analogues had relatively poor affinities (KI ca. 300 nM) for B-type receptors.Compound 9 was the most potent (KI = 0.56 nM) and selective I(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.
