Neurochemical studies of an analgesic, 1,3-diphenyl-5-(2-dimethylaminopropionamide)-pyrazole [difenamizole].
For the purpose of clarifying the action mechanism of the analgesic agent, difenamizole (DFZ), chemically known as 1,3-diphenyl-5-(2-dimethylaminopropionamide)-pyrazole, the following properties were investigated: 1) monoamine metabolizing enzymes, 2) biosynthesis of dopamine (DA), 3) binding of DA on the synaptic membrane of mice, 4) uptake of catecholamine (CA) by synaptosome in discrete brain areas and 5) DA release from the striatal slices of mice. Pertinent results obtained are delineated below: 1) DFZ at 10(-4) M inhibited the monoamine oxidase (MAO) activity to some extent although it had no activity on catechol-O-methyltransferase (COMT) at 10(-6) -10(-4) M. 2) DFZ significantly enhanced the DA accumulating activity of pargyline in the striatum. 3) DFZ inhibited the binding of 3H-DA to synaptic membrane by 25% at 10(-4) M in the striatum. 4) DFZ inhibited the DA uptake by 50% at 10(-4) M though the activity was somewhat weaker than imipramine or cocaine on the striatum. 5) DFZ inhibited the DA release due to high K+ concentration in striatal slices at 10(-4) -5x10(-4) M. From the above data, it was concluded that DFZ may exert its analgesic effect by inhibiting the release of DA and preventing the binding of DA with the receptors.
D000251:Adenosine Triphosphatases / Q000032:analysis; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D065098:Catechol O-Methyltransferase Inhibitors; D002395:Catecholamines / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D013574:Synaptosomes / Q000378:metabolism
D000700:Analgesics; D065098:Catechol O-Methyltransferase Inhibitors; D002395:Catecholamines; D008996:Monoamine Oxidase Inhibitors; D011720:Pyrazoles; C001083:difenamizole; D000251:Adenosine Triphosphatases; D011188:Potassium; D004298:Dopamine