title: Pharmacological effects of enantiomers of 4-amino-N-(alpha-methylbenzyl)benzamide, a chemically novel anticonvulsant.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: J D
authors.initials: JD
authors.lastname: Leander
authors.forename: D W
authors.initials: DW
authors.lastname: Robertson
authors.forename: C R
authors.initials: CR
authors.lastname: Clark
authors.forename: R R
authors.initials: RR
authors.lastname: Lawson
authors.forename: R C
authors.initials: RC
authors.lastname: Rathbun
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use* / Q000633:toxicity; D002220:Carbamazepine / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010634:Phenobarbital / Q000627:therapeutic use; D010672:Phenytoin / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D013237:Stereoisomerism
chemical_list: D001549:Benzamides; D002220:Carbamazepine; D010672:Phenytoin; C054763:LY 188544; D010634:Phenobarbital