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

The pyridopyrimidine derivative IQM‐95,333 ((4a S ,5 R )‐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. IQM‐95,333 displaced [ 3 H]‐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 (IC 50 >10 μ M ). IQM‐95,333 was a more selective CCK A receptor ligand than devazepide and other CCK A receptor 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 CCK A receptors. 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 (IC 50 s around 20 n M ) 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 CCK A receptors. 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. 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 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.British Journal of Pharmacology (1997) 121 , 759–767; doi: 10.1038/sj.bjp.0701186