Part 2. Long term in vivo/in vitro evaluation of the Cholecystokinin antagonists: N-(5-methyl-3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-N'-phenylurea MPP and carboxamide MPM.

The mixed CCK antagonist N-(3-oxo- 2,3-dihydro-1H-pyrazol-4-yl)-indole-carboxamide MPP with a binding affinity of 25nM /20nM and the CCK1 selective 3-oxo-1,2-diphenyl-2,3-dihydro-1Hpyrazol- 4-yl)-N'-phenyl-urea MPM (IC50 = 25nM) represent the best two compounds of an amide and a urea pyrazoline series, which were previously evaluated in mice (Part 1) for their CNS activity. The long term in vivo and in vitro evaluation is described in this part. Stress was induced for a 4 week period daily. A dose of 0.5 mg/kg of MPP and MPM showed a significant antidepressant effect in the foced swim test in rats, which was in enhanced within a 4 week test period. The mixed CCK antagonist MPM only occurred anxiolytic properties in the elevated X-maze in rats at a 0.5 mg/kg dose. For the stress induced rats, the MPP and MPM treatment reversed the effects of stress on the dendritic atrophy in hippocampal CA3 pyramidal neurons. A reduction of organ weight was reversed for the adrenal gland, when the animals were treated with the CCK antagonists MPP and MPM over a period of 4 weeks.