Synthesis and evaluation of N-(5-methyl-3-oxo-1,2- diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-N'-phenylureas as cholecystokinin antagonists.
In the search for new cholecystokinin (CCK) ligands, ureidopyrazolines were identified in combinatorial libraries using 168 chemically diverse amines. The structure-activity relationship optimisation of this pyrazoline template 4a resulted in novel 3-oxo-1,2-diphenyl-2,3-di-hydro-1H-pyrazol-4-yl)-N'-phenylureas 5a-5o. These novel CCK ligands have shown to act as mixed CCK-A/CCK-B ligands in a [125]I-CCK-8 receptor binding assay. The best pyrazoline 5e of this series displayed an IC50 of 20 and 25 nmol/L for the CCK-A, and CCK-B receptor, respectively. In a subsequent in vivo evaluation using various behavior pharmacological assays, an anxiolytic effect of these novel diphenylpyrazolinyl ureas was found in the elevated x-maze with an ED50 of 1.7 mg/kg. In the despair swimming test, a model for testing antidepressants, an ED50 of 0.69 mg/kg was determinated for urea 5e and the antidepressant effect had a magnitude comparable to desimipramine.
Lattmann
Eric
E
School of Pharmacy, Aston University, Birmingham, England. e.lattmann@aston.ac.uk
Sattayasai
Jintana
J
Boonprakob
Yodchai
Y
Lattmann
Pornthip
P
Singh
Harjit
H
D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D018737:Hand Strength / Q000502:physiology; D019417:Hindlimb Suspension; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D012844:Sincalide / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013550:Swimming
D000700:Analgesics; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D007202:Indicators and Reagents; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin; D012844:Sincalide