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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 -1,3dioxoperhydropyridol[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.