145963-08-2Relevant articles and documents
Role of N- and C-terminal substituents on the CCK-B agonist - Antagonist pharmacological profile of Boc-Trp-Phg-Asp-Nal-NH2 derivatives
Weng, Jian Hui,Blommaert, Armand G.S.,Moizo, Laurent,Bado, Andre,Ducos, Bertrand,Boehme, Andreas,Garbay, Christiane,Roques, Bernard P.
, p. 563 - 573 (2007/10/03)
Among the CCK derivatives, the tetrapeptide Boc-Trp-Phg-Asp-Nal-NH2 (1) behaves as a short potent CCK-B agonist which led to the development of an efficient peptidase-resistant CCK-B antagonist by bismethylation of its terminal CONH2 group. Further modifications of the N-and C-terminal moieties of 1 have been performed and are described in this paper, together with the pharmacological profile of the novel synthesized compounds. Introduction of more bulky substituents than NalNH2 on the C-terminal part decreased the CCK-B receptor binding affinity. In the series of N-protected tetrapeptides X30-Phg31-Asp32-Nal33-N(CH 3)2, the Boc-substituent was shown to be optimal among the N-protecting groups Boc, 2Adoc, propionyl or acetyl when X = Trp. On the other hand, when X = αMcTrp, its optimal N-protecting group was 2Adoc and its configuration was preferentially D. In the newly synthesized compounds, 13: 2Adoc-D-αMeTrp-Phg-Asp-NalN(CH3)2 and 16: 2Adoc-D-αMeTrp-Phg-Asp-NalNH2 had the best CCK-B receptor affinities (K1 = 3.5 and 3.4 nM, respectively) and were selected for further biological evaluation. Interestingly, when tested for their capacity to influence inositol phosphate formation, induced by CCK8 in CHO cells transfected with the rat CCK-B receptor, compound 13 behaved as a full CCK-B antagonist with an IC50 value of 18 ± 1 nM, being as potent as the antagonists L-365,260 and PD-134,308 (IC50 values respectively, 39 ± 17 and 30 ±2 nM), whereas compound 16 was found to behave as a partial CCK-B agonist. Indeed 16 behaved as an antagonist on the firing rate of rat CA1 hippocampal neurons and acted as an agonist in the pentagastrin stimulated gastric acid secretion (EC50 = 12 nmol/kg) in anesthetized rats. Compound 13 in contrast, was found to inhibit the pentagastrin action at a dose (ID50 = 0.56 μmol/kg) similar to the potent antagonist PD-134,308 (ID50 = 0.4 μmol/kg). The antagonist/agonist properties of compounds 13 and 16 show that both N-and C-terminal substituents modulate the pharmacological properties in the Boc-CCK4 derivatives presented here. Copyright
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.
