Pharmacological evaluation of IQM-95,333, a highly selective CCK_A receptor antagonist with anxiolytic-like activity in animal models

Abstract

1. The pyridopyrimidine derivative IQM-95,333 ((4aS,5R)-2-benzyl-5-[N^α-tert-butoxicarbonyl)L-tryptophyl]amino-1,3dioxoperhydropyrido[1,2-c]pyrimidine), a new non-peptide antagonist of cholecystokinin type A (CCK_A) receptors, has been evaluated in vitro and in vivo in comparison with typical CCK_A and CCK_B receptor antagonists, such as devazepide, lorglumide, L-365,260 and PD-135,158.

2. IQM-95,333 displaced [³H]-CCK-8S binding to CCK_A receptors from rat pancreas with a high potency in the nanomolar range. Conversely, the affinity of this new compound at brain CCK_B receptors was negligible (IC₅₀>10 μM). IQM-95,333 was a more selective CCK_A receptor ligand than devazepide and other CCK_A receptor antagonists.

3. Like devazepide, IQM-95,333 was a more potent antagonist of CCK-8S- than of CCK-4-induced contraction of the longitudinal muscle from guinea-pig ileum, suggesting selective antagonism at CCK_A receptors.

4. IQM-95,333 and devazepide were also potent inhibitors of CCK-8S-stimulated amylase release from isolated pancreatic acini, a CCK_A receptor-mediated effect. The drug concentrations required (IC₅₀s around 20 nM) were higher than in binding studies to pancreas homogenates.

5. Low doses (50–100 μg kg⁻¹, i.p.) of IQM-95,333 and devazepide, without any intrinsic effect on food intake or locomotion, blocked the hypophagia and the hypolocomotion induced by systemic administration of CCK-8S, two effects associated with stimulation of peripheral CCK_A receptors.

6. IQM-95,333 showed an anxiolytic-like profile in the light/dark exploration test in mice over a wide dose range (10–5,000 μg kg⁻¹). Typical CCK_A and CCK_B antagonists, devazepide and L-365,260 respectively, were only effective within a more limited dose range.

7. In a classical conflict paradigm for the study of anxiolytic drugs, the punished-drinking test, IQM-95,333, devazepide and L-365,260 were effective within a narrow dose range. The dose-response curve for the three drugs was biphasic, suggesting that other mechanisms are operative at higher doses.

8. In conclusion, IQM-95,333 is a potent and selective CCK_A receptor antagonist both in vitro and in vivo with an anxiolytic-like activity in two different animal models, which can only be attributed to blockade of this CCK receptor subtype.

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