A comparison of prodrug esters of nipecotic acid

The relative ability of the enantiomers of the ethyl and m-nitrophenyl esters of nipecotic acid to block convulsions induced by bicuculline and pentylenetetrazol, as well as to block the uptake of GABA into whole brain mini-slices, was studied in mice. Neither (+)ethyl nipecotate hydrogen tartrate [(+)E.Tartrate], which is hydrolyzed to (-)nipecotic acid, nor (-)ethyl nipecotate hydrogen tartrate [(-)E.Tartrate], which is hydrolyzed to (+)nipecotic acid, provided protection against challenge with bicuculline. Both (+)E.Tartrate and (-)ethyl nipecotate hydrochloride [(-)E.HCl], which are hydrolyzed to (-)nipecotic acid, blocked seizures induced by pentylenetetrazol. However, neither (-)E.Tartrate nor (+)ethyl nipecotate hydrochloride [(+)E.HCl], which are hydrolyzed to (+)nipecotic acid, provided significant protection against challenge with pentylenetetrazol. These results agree with the relative ability of these compounds to inhibit the uptake of GABA, where (-)nipecotic acid was more potent than (+)nipecotic acid and (+)E.Tartrate was more potent than (-)E.Tartrate. The enantiomers of m-nitrophenyl-3-piperidinecarboxylate hydrochloride, (+)MNPC.HCl and (-)MNPC.HCl, were almost equi-effective in preventing seizures induced by bicuculline. This lack of significant difference in anticonvulsant activity is in contrast with the ability to inhibit the uptake of GABA, where (-)MNPC.HCl was significantly more potent than (+)MNPC.HCl. Changing the route of administration from subcutaneous to intraperitoneal injection reduced the onset of time of the peak effect and the anticonvulsant potency of (+/-)MNPC.HCl. Cholinergic effects were observed with the administration of (+)E.Tartrate and (-)E.HCl, but not with (-)E.Tartrate, (+)E.HCl, (+)MNPC.HCl or (-)MNPC.HCl.(ABSTRACT TRUNCATED AT 250 WORDS)