Comparative studies on the anticonvulsant activity of lipophilic derivatives of gamma-aminobutyric acid and 2-pyrrolidinone in mice.
Anticonvulsant activity, degradation into gamma-aminobutyric acid (GABA), and concentration in brain of 1-dodecanoyl-2-pyrrolidinone (I), a lipophilic derivative of a lactam of GABA, were compared with those of N-dodecanoyl GABA (II) and 1-dodecyl-2-pyrrolidinone (III) to get information about their pharmacological mechanisms. Compounds I and II degraded into GABA in mouse liver homogenate, gradually into GABA in brain homogenate and more slowly in plasma. Compound III had no degradation in the biological media. The derivatives administered intraperitoneally had dose-dependent anticonvulsant activity on picrotoxin-induced seizure in mice. Their anticonvulsant activities were changed by the time intervals between pretreatment of derivatives and administration of picrotoxin. Compounds II and III showed anticonvulsant activity on pentylenetetrazole-induced seizure and a prolonged sleeping time induced by sodium pentobarbital in mice. However, these three derivatives never significantly increased the GABA level in mouse brain after intraperitoneal administration compared to the endogenous GABA level. They were detected as intact derivatives in the brain. In the previous report, we demonstrated the anticonvulsant activity of sodium dodecanoate. These results suggested that the dodecyl chain of derivatives may be important for their anticonvulsant activities and I does not act as GABA via prodrug.
Nakamura
J
J
School of Pharmaceutical Sciences, Nagasaki University, Japan.
Miwa
T
T
Mori
Y
Y
Sasaki
H
H
Shibasaki
J
J
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D004355:Drug Stability; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011355:Prodrugs / Q000378:metabolism*; D011760:Pyrrolidinones / Q000378:metabolism / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
D000927:Anticonvulsants; D011355:Prodrugs; D011760:Pyrrolidinones; C065136:1-lauryl-2-pyrrolidone; C070104:N-dodecanoyl-4-aminobutyric acid; D005680:gamma-Aminobutyric Acid; C070103:1-dodecanoyl-2-pyrrolidinone