LY 188544,S,R-4-amino-N-(alpha-methylbenzyl)
benzamide, and its two stereoisomers are structurally novel
anticonvulsants. The
anticonvulsant profile of
LY 188544 after intraperitoneal administration to mice was determined in standard
anticonvulsant tests: maximal electric
shock (MES),
strychnine tonic-extensor, and threshold tests using
pentylenetetrazol,
picrotoxin, and
bicuculline. In this series of tests,
LY 188544 had good activity in the MES test and some activity in the three threshold tests. Thus, its profile of activity was most similar to that of
phenobarbital, and less similar to that of
phenytoin and
carbamazepine. After
oral administration to mice and rats, LY188544 was effective in the MES test, but did not provide complete protection in the threshold
pentylenetetrazol test. When the individual stereoisomers, LY188545 (S isomer) and LY188546 (R isomer), were evaluated after
oral administration, LY188545 was 2.2 times more potent than LY188546 against MES-induced
seizures. However, when evaluated after
intravenous administration, the potency difference was only 1.1. LY188546 was the least toxic in terms of neurological impairment. All compounds had good protective indexes (ratio between doses for neurological impairment and doses for
anticonvulsant efficacy in the MES test). LY188545 and LY188546 potentiated
hexobarbital sleeping time after acute administration but not after chronic (4-day) administration. Tolerance did not develop to the effects of LY188546 on MES or neurological impairment after 4 days of administration. These results suggest that LY188546 is a chemically novel
anticonvulsant with a promising pharmacological profile.