Drug Discov Ther. 2008;2(3):156-167.

Cholecystokinin antagonists (part 1): Antinociceptive, anxiolytic and antidepressant effects of N-(5-methyl-3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-N'-phenylureas and carboxamides.

Lattmann E, Sattayasai J, Boonprakob Y, Singh H, Lattmann P, Dunn S


The SAR optimization of the pyrazoline template resulted in novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamides and novel 3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-N'-phenylureas. These non-peptidal heterocyclic compounds have shown to bind as potent CCK1 selective and mixed CCK antagonists in a [125I]CCK-8 receptor binding assay. The best amides 3c and 3d of this series displayed an IC50 of 20 and 25 nM for the CCK1 receptor, respectively. The best ureidopyrazoline 4b and 4e of this series displayed an IC50 of 20 and 25 nM, as a mixed CCK receptor antagonist. In the elevated x-maze an anxiolytic effect of the urea 4e was found from 10 μg/kg upwards for the mixed antagonist. In the despair swimming test, a model for testing antidepressants, both mixed and CCK1 selective antagonists were found active as a modulator over a big range from from 10-500 μg/kg and the magnitude of the effects were comparable to desimipramine. The amides and the phenylureas enhanced significantly the analgesic effect of morphine over a wide dose range in mice.

KEYWORDS: CCK-antagonists, N-(3-Oxo-2,3-dihydro-1Hpyrazol-4-yl)-indole-carboxamides, 3-Oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-N'-phenyl ureas, Elevated plus-maze, Forced swim test, Tail immersion test

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