Triazolines XV. Anticonvulsant profile of ADD 17014, a potentially unique 1,2,3-triazoline antiepileptic drug, in mice and rats.
ADD 17014[1-(4-chlorophenyl)-5-(4-pyridyl) delta 2-1,2,3-triazoline], is a representative member of a hitherto unknown, structurally novel family of anticonvulsant agents. The anticonvulsant profile of ADD 17014 following intraperitoneal (i.p.) and oral administration in mice and rats was evaluated using a battery of well-standardized anticonvulsant tests and compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). The results indicate that ADD 17014 is effective in nontoxic i.p. doses in mice by the maximal electroshock seizure (MES), Metrazol (subcutaneous, s.c. Met), bicuculline (s.c. Bic) and picrotoxin (s.c. Pic) tests, but ineffective against strychnine-induced seizures; it is also effective after nontoxic oral doses in both mice and rats by the MES and s.c. Met tests. Protective indices (PI = TD50/ED50), calculated from i.p. data in mice, were highest for ADD 17014 by the s.c. Met (26.02) and s.c. Bic (93.93) tests; the PIs, after oral administration in mice and rats, were equal to or higher than those of the prototype agents. In vitro receptor binding studies of ADD 17014 and potential metabolites indicated no significant inhibitory activity except for the beta-amino alcohol, which displaced almost 93% of [3H]glutamate from the glutamate receptors, suggesting that ADD 17014 may be functioning as a prodrug and an excitatory amino acid antagonist. The overall results indicate that ADD 17014 is a relatively nontoxic agent that more closely resembles PB and VPA, with a broad and unique spectrum of anticonvulsant activity.
Kadaba
P K
PK
Division of Medicinal Chemistry, College of Pharmacy, University of Kentucky, Lexington 40536-0084.
Slevin
J T
JT
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D005445:Flunitrazepam / Q000378:metabolism; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009420:Nervous System / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity
D000927:Anticonvulsants; D014230:Triazoles; C055990:ADD 17014; D005445:Flunitrazepam