1-(substituted benzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidones: a series with stimulant and depressant activities.
A series of 1-(substituted benzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidones was synthesized primarily by catalytic hydrogenation of the corresponding 1-(substituted benzyl)-2(1H)-pyrimidone. The pharmacological evaluation of these compounds in mice revealed a unique profile that included evidence of CNS stimulation and depression within the series and in the same compounds. Some members of this series induced signs of only CNS stimulation, some compounds caused signs of only CNS depression and skeletal muscle relaxation, and some caused signs of both stimulation and depression in the same animal. This apparent dual activity was assessed further in mice with antidepressant tests based on tetrabenazine antagonism and with antianxiety/anticonvulsant tests on the antagonism of a number of convulsants. The 4-chloro-, 4-fluoro-, 4-bromo-, and 3,4-dichlorobenzyl compounds exhibited antidepressant and antianxiety activities in the same dose range. Among these four compounds, the 3,4-dichlorobenzyl compound possessed the lowest antitetrabenazine (17 mg/kg po) and antipentylenetetrazol (23 mg/kg po) ED50 values. The 4-fluoro compound antagonized tetrabenazine-, pentylenetetrazol-, and isoniazid-induced tonic convulsions in the same dose range (congruent to 50 mg/kg po).
D000818:Animals; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001921:Brain / Q000187:drug effects*; D055598:Chemical Phenomena; D002621:Chemistry; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D013747:Tetrabenazine / Q000037:antagonists & inhibitors
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D011744:Pyrimidinones; D010433:Pentylenetetrazole; D013747:Tetrabenazine