The Synthesis of Novel GABA Uptake Inhibitors. 1. Elucidation of the Structure-Activity Studies Leading to the Choice of (R)-1--3-piperidinecarboxylic Acid (Tiagabine) as an Anticonvulsant Drug Candidate

Article abstract of DOI:10.1021/jm00064a005

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 <³H>-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/heteroatomic 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.