Synthesis, stability, and pharmacological evaluation of nipecotic acid prodrugs

Nipecotic acid (1), one of the most potent in vitro inhibitors of neuronal and glial gamma-amino butyric acid (GABA) uptake, is inactive as an anticon vulsant when administered systemically. To obtain in vivo active prodrugs o f (1), we synthesized four new nipecotic acid esters (3-6), which were obta ined by chemical conjugation with glucose, galactose, and tyrosine. These c ompounds were assayed to evaluate their in vitro chemical and enzymatic hyd rolysis. In addition, their anticonvulsant activity was evaluated in vivo i n Diluted Brown Agouti (DBA)/2 mice, an excellent animal model for the stud y of new anticonvulsant drugs. Esters (3-6) appeared stable, at various tem peratures, in a pH 7.4 buffered solution and showed susceptibility to under going in vitro enzymatic hydrolysis. Intraperitoneally injected nipecotic a cid (1) and esters (3-5) did not protect mice against audiogenic seizures; conversely, nipecotic tyrosine ester (6) showed a significant dose-dependen t anticonvulsant activity. The in vivo protective activity of the ester (6) and the inefficiency of nipecotic acid (1) in the same experimental condit ions suggest that this ester prodrug could be actively transported intact a cross the blood-brain barrier, beyond which it could be hydrolyzed.