gamma-Aminobutyric acid uptake inhibition and anticonvulsant activity of nipecotic acid esters.
n-Alkyl esters of nipecotic acid were prepared by Fischer esterification, and the esters were evaluated against bicuculline-induced seizures in mice. Evaluation of the alkyl esters for inhibition of gamma-aminobutyric acid uptake into mouse whole brain mini-slices revealed that the order of potency was proportional to chain length. The octyl ester inhibited gamma-aminobutyric acid and beta-alanine uptakes by apparently nonspecific mechanisms. A variety of phenyl esters of nipecotic acid were also synthesized utilizing either dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole as the condensing agent. Most of the phenyl esters were potent inhibitors of gamma-aminobutyric acid uptake. The uptake inhibition appeared to involve specific and nonspecific (detergent-like) mechanisms. The m-nitrophenyl and p-nitrophenyl esters were particularly potent against bicuculline-induced seizures in mice.
D000409:Alanine / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline / Q000037:antagonists & inhibitors / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018756:GABA Antagonists; D008297:Male; D051379:Mice; D009557:Nipecotic Acids / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced; D012995:Solubility; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000927:Anticonvulsants; D018756:GABA Antagonists; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; D000409:Alanine; D001640:Bicuculline