Synthesis and evaluation of N-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1H-indole-carboxamides as cholecystokinin antagonists.
The structure-activity relationship optimization of the pyrazoline template 3a resulted in novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamides 4a-4e. These non-peptidal CCK ligands have been shown to act as potent CCK1 ligands in a [125]I-CCK-8 receptor binding assay. The best amides (4c and 4d) of this series displayed an IC50 of 20/25 nM for the CCK1 receptor. In a subsequent in-vivo evaluation using various behaviour pharmacological assays, an anxiolytic effect of these novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamides was found at high doses in the elevated plus-maze. In the despair swimming test, a model for testing antidepressants, an ED50 of 0.33/0.41 mg kg(-1) was determined for amide 4c/4d and the antidepressant effect had a magnitude comparable to desimipramine.
The School of Pharmacy, Aston University, Aston Triangle, Birmingham B4 7ET, UK. e.lattmann@aston.ac.uk
Eric
E
Lattmann
Harjit
H
Singh
Yodchai
Y
Boonprakob
Pornthip
P
Lattmann
Jintana
J
Sattayasai
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000577:Amides; D000700:Analgesics; D000928:Antidepressive Agents; D007211:Indoles; D011720:Pyrazoles; D043886:Receptor, Cholecystokinin A