Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin.

Abstract

We describe the design and synthesis of nonpeptidal antagonists of the peptide hormone cholecystokinin. Several of these compounds have high specificity and nanomolar binding affinity and are active after oral administration. To our knowledge, the design of such agents has not previously been accomplished for any peptide hormone. The structural similarities between these synthetic compounds and the anxiolytic 1,4-benzodiazepines are noted, and the potential of this structural feature for future design of ligands for other peptide hormone receptors is discussed.selective nonpeptidal antagonist of CCK in vitro and in vivo (7). However, asperlicin has liabilities as a pharmacological or potential therapeutic agent, including lack of oral bioavailability, modest potency, and poor water solubility (7, 42).Many important drugs such as ivermectin (18)

The effect of CCKB/gastrin antagonists on stimulated gastric acid secretion in the anaesthetized rat

“…The effect of this CCKB/gastrin antagonist was relatively weak compared to PD 136450, whilst the selective CCKA antagonist devazepide was inactive at up to 300pumolkg-1 against the three stimulants. This latter observation is in keeping with the low affinity of devazepide for both the gastrin, and brain CCKB receptors (Chang & Lotti, 1986;Evans et al, 1986). However, our results with devazepide are in conflict with those in a similar study by Hirst et al (1991).…”

“…However, neither the specificity nor the affinity of proglumide has been sufficient to permit its use in vivo to define the role of gastrin in the regulation of gastric acid secretion. In recent years other CCK receptor antagonists from several chemical classes have been developed, and although there are now available such benzodiazepines as devazepide 718 Chang & Lotti, 1986;Evans et al, 1986) with high affinity and high selectivity 'Author for correspondence.…”

Cross-interactions of Two p38 Mitogen-activated Protein (MAP) Kinase Inhibitors and Two Cholecystokinin (CCK) Receptor Antagonists with the CCK1 Receptor and P38 MAP Kinase

“…9D) confirmed that L364,718 and L365,260 were not only CCK receptor antagonists but also behaved as specific and direct p38 MAP kinase inhibitors. L364,718 is a specific CCK1 receptor antagonist (45), whereas L365,260 is a specific CCK2 receptor antagonist, and both interact with p38 MAP kinase. SB202190 and SB203580 interact specifically with the CCK1 receptor but not with the CCK2 receptor.…”

[D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, a potent bombesin antagonist in murine Swiss 3T3 cells, inhibits the growth of human small cell lung cancer cells in vitro

“…The cells achieve 10-fold increase in number in -12 days in serum-free medium (Inset). Both antagonists inhibited growth in a dose-dependent manner; half-maximal effect was seen with 24 ,uM (17,(34)(35)(36), but designing antagonists remains problematic. Unexpectedly, the substance P antagonist peptide A, which has minimal structural homology with bombesin, was found to be an antagonist for bombesin-stimulated enzyme secretion from dispersed pancreatic acini (17) and to block its growth-stimulatory effects (3,18).…”