Synthesis and anticonvulsant activity of 3-(3'-trifluoromethylphenoxy)-pyridines and -dihydropyridines.
3-(3"Trifluoromethylphenoxy)-1,4-dihydropyridines containing phenoxycarbonyl, methoxycarbonyl or acetyl at the 1 position, and phenyl, n-butyl or methyl at the 4-position were synthesised (generalised structure 4). Four members of this series (4a-c, 4g)--the rest were not evaluated because of their facile oxidation to pyridines--were found to be inactive in maximal electroschock (MES) and subcutaneous pentylenetetrazole (scPTZ) screening tests in mice, suggesting that the 1-carbonyl-3-(3'-trifluoromethyl-phenoxyl)-1,4-dihydropyridyl++ + moiety is not a suitable anticonvulsant pharmacophore. 4-Phenyl-3-(3'-trifluoromethylphenoxy)pyridine (5a)--the oxidation product of 4a--was also inactive in both tests. In contrast, the isomeric 2-phenyl-3-(3'-trifluoromethylphenoxy)pyridine (7), whilst inactive in the scPTZ test, exhibited significant anticonvulsant activity in the mouse MES test (intraperitoneal administration; ED50 = 159 mg/kg), and increased activity following its oral administration in a rat MES test (ED50 = 31.9 mg/kg). It caused displacement of 10 microM [3H]flunitrazepam from mouse whole brain P2 pellets at 30 microM concentration, indicating low affinity for the benzodiazepine receptor(s).
Phillips
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Knaus
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D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D004597:Electroshock; D005445:Flunitrazepam / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism
D000927:Anticonvulsants; D004095:Dihydropyridines; D011725:Pyridines; D011963:Receptors, GABA-A; D005445:Flunitrazepam; D010433:Pentylenetetrazole