RESUMO
Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK2-selective ligands using radiolabelled binding assays. CCK antagonism was confirmed for the ligands in isolated tissue preparations. DSS (dextran sulfate sodium)-induced inflammation was analysed for derivative 7 and PNB-001 with L-365,260 as a standard. The IC50 of PNB-001 was determined to be 10 nM. Subsequent in vivo evaluation confirmed anti-inflammatory activity with respect to IBD assays. The best molecule, PNB-001, showed analgesic activity in the formalin test and in the hotplate assay, in which the analgesic effect of 1.5 mg kg-1 PNB-001 was equivalent to 40 mg kg-1 tramadol. The CCK2-selective antagonist PNB-001 protected rats against indomethacin-induced ulceration at similar doses. The GI protection activity was found to be more potent than that of the 10 mg kg-1 dose of prednisolone, which served as a standard.
RESUMO
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 [(125)I]CCK-8 receptor binding assay. The best amides 3c and 3d of this series displayed an IC(50) of 20 and 25 nM for the CCK(1) receptor, respectively. The best ureidopyrazoline 4b and 4e of this series displayed an IC(50) 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 CCK(1) 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.
RESUMO
Various 1,4-benzodiazepines were synthesized around a Diazepam, Oxazepam and the n-propyl-1,4-benzodiazepine template. SAR studies of CCK(2) binding affinity were performed and selected examples of each series were tested in vivo in mice. In addition to an anxiolytic effect, antidepressant effects were discovered using 8 standard CNS assays in mice. Finally, the cocomittant administration of the 1,4-benzodiazepine based CCK antagonists enhanced the response to pain with a low dose of morphine, significantly.
RESUMO
BACKGROUND: Expert appraisals of vestibular disorders and their effects on daily life are essentially based on an evaluation of the patient's subjectively described symptoms. The aim of the present study was to ascertain the extent to which dynamic posturography is able to assist in the preparation of expert's reports. MATERIAL AND METHODS: 60 patients underwent a survey of their balance impairment. Both a nystagmus analysis, with its objective criteria, and dynamic posturography were carried out. The investigation into reduction of fitness for work (MdE) made reference to the criteria specified in the table by STOLL. The data obtained were subjected to both correlation and variance analysis. RESULTS: Although the results of this analysis revealed no direct statistical dependency, they indicated a tendency for the composite values to be correlated with the nystagmus scores and/or the MdE values (when the nystagmus score and/or the MdE increases, the composite value decreases). CONCLUSIONS: The Equitest is, according to the available data, not able to replace the currently valid MdE scores. Nevertheless, it represents a means of providing objective data about the vestibulo-spinal reflex. The test also reveals any tendencies towards simulation and aggravation. In the context of a specific nystagmus analysis, the Equitest offers an additional means of providing an objective background to back up the more subjective assessment of MdE.
