Biochemical and pharmacological characterization of an extremely potent and selective nonpeptide cholecystokinin antagonist.

Abstract

3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-IH-1,4-benzodiazepine-3-yl)-lH-indole-2-carboxamide (L-364,718) interacted in a competitive manner with rat pancreatic cholecystokinin (CCK) receptors as determined by Scatchard analysis of the specific binding of '21I-labeled CCK. The affinity of L-364,718 for both pancreatic (IC50, 81 pM) and gallbladder (IC50, 45 pM) CCK receptors in radioligand binding assays greatly exceeded that of other reported nonpeptide CCK antagonists and was similar to that of CCK itself. In vitro functional studies utilizing CCK-induced contractions of the isolated guinea pig ileum and colon further demonstrated that L-364,718 acts as a competitive CCK antagonist, which lacks agonist activity and has a similar high affinity in these tissues (pA2, 9.9). L-364,718 exhibited a very high selectivity for peripheral CCK receptors relative to brain CCK, gastrin, and various other peptide and nonpeptide receptors in both in vitro radioligand and isolated tissue assays.In vivo, low intravenous doses of L-364,718 (0.1 mg/kg) markedly antagonized the contractions of the guinea pig gallbladder produced by intravenous administration of CCK for at least 2 hr. Administered orally, L-364,718 (ED50, 0.04 mg/kg) was highly effective as an antagonist of CCK-induced inhibition of gastric emptying in mice. The biochemical and pharmacological properties of L-364,718-namely, very high affinity and selectivity for peripheral CCK receptors, longlasting in vivo efficacy, and oral bioavailability-makes this compound a powerful tool for investigating the physiological and pharmacological actions of CCK, and possibly its role in gastrointestinal disorders.

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).…”

“…All other antagonists tested had no effect upon basal acid secretion. Recently, non-peptide agents of the benzodiazepine structure with high affinity for peripheral CCKA receptors and only low affinity for gastrin and CCKB receptors have been described (Chang et al, 1985;Chang & Lotti, 1986). The related compound with the reverse profile of affinity, L-365,260, was subsequently described (Bock et al, 1989;Lotti & Chang, 1989 active in producing a dose-dependent block of pentagastrininduced acid secretion in the anaesthetized rat, confirming observations of Lotti & Chang (1989) in the anaesthetized mouse and conscious rat following oral or intraduodenal administration.…”

“…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.…”

Pharmacological profile of TP‐680, a new cholecystokininA receptor antagonist

“…CCK receptors are classified into type A (peripheral) and type B (central), depending on the structural specificity expressed and the relative affinities for various members of the CCK-gastrin family (Moran et al, 1986). Recently, highly potent and specific antagonists for the peripheral CCKA receptors have been reported (Makovec et al, 1985;Chang & Lotti, 1986;Akiyama & Otsuki, 1994). MK-329 (formerly termed L-364,718) is considered the most potent and highly specific CCK antagonist and is used to characterize the peripheral CCKA receptors (Otsuki et al, 1988;Niederau et al, 1989).…”

Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine

“…CCK interacts with at least two distinct types of receptor (Innis & Snyder, 1980;Moran et al, 1986;Wank et al, 1992): CCKB receptors, which represent the predominant form in the rodent CNS (Pelaprat et al, 1987;Hill & Woodruff, 1990) and CCKA receptors, the abundant form in peripheral tissues (Zetler, 1984;Van Dijk et al, 1984;Chang & Lotti, 1986) but are also found in discrete nuclei of the CNS (Hill et al, 1987a;. Molecular cloning and pharmacological studies have demonstrated a close relationship between CCKB and gastrin receptors found mainly in the parietal cells of the gastric mucosa (Chang et al, 1989;Pisegna et al, 1992;Hunter et al, 1993).…”