A comparison of prodrug esters of nipecotic acid

Abstract

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·HC1], 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·HC1 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·HC1, (+)MNPC·HCl or (-)MNPC·HCl. Some protection was provided by (+)MNPC·HCl against convulsions induced by strychnine, however, the ED50 value of 489.8 mg/kg was almost four times the ED50 value of 129.6 mg/kg for seizures induced by bicuculline. © 1988.