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 ((4aS,5R)-2-benzyl-5-[N alpha-tert-butoxicarbonyl)L-tryptophyl] amino-1,3dioxoperhydropyrido[1,2-c]pyrimidine), a new non-peptide antagonist of cholecystokinin type A (CCKA) receptors, has been evaluated in vitro and in vivo in comparison with typical CCKA and CCKB receptor antagonists, such as devazepide, lorglumide, L-365,260 and PD-135,158. 2. IQM-95,333 displaced [3H]-CCK-8S binding to CCKA receptors from rat pancreas with a high potency in the nanomolar range. Conversely, the affinity of this new compound at brain CCKB receptors was negligible (IC50 > 10 microM). IQM-95,333 was a more selective CCKA receptor ligand than devazepide and other CCKA 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 CCKA receptors. 4. IQM-95,333 and devazepide were also potent inhibitors of CCK-8S-stimulated amylase release from isolated pancreatic acini, a CCKA 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 micrograms 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 CCKA 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 micrograms kg-1). Typical CCKA and CCKB 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 CCKA 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.
Ballaz
S
S
Department of Physiology and Pharmacology, University of Navarra, Pamplona, Spain.
Barber
A
A
Fortuño
A
A
Del Río
J
J
Martin-Martínez
M
M
Gómez-Monterrey
I
I
Herranz
R
R
González-Muñiz
R
R
García-López
M T
MT
D000681:Amylases / Q000378:metabolism; D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology*; D002766:Cholecystokinin / Q000378:metabolism*; D020109:Devazepide; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D005277:Fenfluramine / Q000494:pharmacology; D006168:Guinea Pigs; D006727:Hormone Antagonists / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D010671:Phenylurea Compounds; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D000681:Amylases; D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D002219:Carbamates; D002766:Cholecystokinin; D020109:Devazepide; D003975:Diazepam; D005277:Fenfluramine; D006727:Hormone Antagonists; D010671:Phenylurea Compounds; D011744:Pyrimidinones; D011949:Receptors, Cholecystokinin; D017367:Selective Serotonin Reuptake Inhibitors; C108038:IQM 95333; C058121:L 365260