THE SYNTHESIS OF NOVEL GABA UPTAKE INHIBITORS .1. ELUCIDATION OF THE STRUCTURE-ACTIVITY STUDIES LEADING TO THE CHOICE OF (R)-1-[4,4-BIS(3-METHYL-2-THIENYL)-3-BUTENYL]-3-PIPERIDINECARBOXYLIC ACID (TIAGABINE) AS AN ANTICONVULSANT DRUG CANDIDATE

A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [H-3]-GABA uptake in rat synaptosomes was determined for each compound. It was found that the most potent examples are those having a substituent in an ''ortho'' position in one or both aromatic/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.