Pharmacological evaluation of IQM‐95,333, a highly selective CCKAreceptor antagonist with anxiolytic‐like activity in animal models

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Abstract
The pyridopyrimidine derivative IQM‐95,333 ((4aS,5R)‐2‐benzyl‐5‐[Nα‐tert‐butoxicarbonyl)L‐tryptophyl]amino‐1,3dioxoperhydropyrido[1,2‐c]pyrimidine), a new non‐peptide antagonist of cholecystokinin type A (CCKA) receptors, has been evaluatedin vitroandin vivoin comparison with typical CCKAand CCKBreceptor antagonists, such as devazepide, lorglumide, L‐365,260 and PD‐135,158. IQM‐95,333 displaced [3H]‐CCK‐8S binding to CCKAreceptors from rat pancreas with a high potency in the nanomolar range. Conversely, the affinity of this new compound at brain CCKBreceptors was negligible (IC50>10 μM). IQM‐95,333 was a more selective CCKAreceptor ligand than devazepide and other CCKAreceptor antagonists. 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 CCKAreceptors. IQM‐95,333 and devazepide were also potent inhibitors of CCK‐8S‐stimulated amylase release from isolated pancreatic acini, a CCKAreceptor‐mediated effect. The drug concentrations required (IC50s around 20 nM) were higher than in binding studies to pancreas homogenates. 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 CCKAreceptors. 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 CCKAand CCKBantagonists, devazepide and L‐365,260 respectively, were only effective within a more limited dose range. 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. In conclusion, IQM‐95,333 is a potent and selective CCKAreceptor antagonist bothin vitroandin vivowith an anxiolytic‐like activity in two different animal models, which can only be attributed to blockade of this CCK receptor subtype. British Journal of Pharmacology(1997)121, 759–767; doi:10.1038/sj.bjp.0701186