PHARMACOLOGICAL EVALUATION OF IQM-95,333, A HIGHLY SELECTIVE CCKA RECEPTOR ANTAGONIST WITH ANXIOLYTIC-LIKE ACTIVITY IN ANIMAL-MODELS

1 The pyridopyrimidine derivative IQM-95,333 zyl-5-[N-alpha-tert-butox icararbonyl)L-tryptophyl] amino-1,3dioxoperhydropyrido[1,2-c]pyrimidin e), a new non-peptide antagonist of cholecystokinin type A (CCKA) rece ptors, has been evaluated in vitro and in vivo in comparison with typi cal CCKA and CCKB receptor antagonists, such as devazepide, lorglumide , L-365,260 and PD-135,158. 2 IQM-95,333 displaced [H-3]-CCK-8S bindin g to CCKA receptors from rat pancreas with a high potency in the nanom olar range. Conversely, the affinity of this new compound at brain CCK B receptors was negligible (IC50 > 10 mu M) IQM-95,333 was a more sele ctive CCKA receptor ligand than devazepide and other CCKA receptor ant agonists. 3 Like devazepide, IQM-95,333 was a more potent antagonist o f CCK-8S- than of CCK-4-induced contraction of the longitudinal muscle from guinea-pig ileum, suggesting selective antagonism at CCKA recept ors. 4 IQM-95,333 and devazepide were also potent inhibitors of CCK-8S -stimulated amylase release from isolated pancreatic acini, a CCKA rec eptor-mediated effect. The drug concentrations required (IC(50)s aroun d 20 nM) were higher than in binding studies to pancreas homogenates. 5 Low doses (50-100 mu g kg(-1), i.p.) of IQM-95,333 and devazepide, w ithout any intrinsic effect on food intake or locomotion, blocked the hypophagia and the hypolocomotion induced by systemic administration o f CCK-8S, two effects associated with stimulation of peripheral CCKA r eceptors. 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 mu g kg (-1)). Typical CCKA and CCKB antagonists, devazepide and L-365,260 res pectively, were only effective within a more limited dose range. 7 In a classical conflict paradigm for the study of anxiolytic drugs, the p unished-drinking test, IQM-95,333, devazepide and L-365,260 were effec tive 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 C CKA receptor antagonist both in vitro and in vivo with an anxiolytic-l ike activity in two different animal models, which can only be attribu ted to blockade of this CCK receptor subtype.