THE SYNTHESIS OF NOVEL GABA UPTAKE INHIBITORS .1. ELUCIDATION OF THE STRUCTURE-ACTIVITY STUDIES LEADING TO THE CHOICE OF ETHYL-2-THIENYL)-3-BUTENYL]-3-PIPERIDINECARBOXYLIC ACID (TIAGABINE) AS AN ANTICONVULSANTDRUG CANDIDATE

A series of different synthetic approaches to novel GABA uptake inhibi tors are described, leading to examples which are derivatives of nipec otic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-buteny l or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibit ion of [H-3]-GABA uptake in rat synaptosomes was determined for each c ompound. It was found that the most potent examples are those having a substituent in an ''ortho'' position in one or both aromatic/heteroar omatic groups. The majority of the compounds described are structurall y related to tiagabine, ethyl-2-thienyl)-3-butenyl]-3-piperidinecarbox ylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.