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

J Med Chem. 1993 Jun 11;36(12):1716-25. 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/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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology
  • GABA Antagonists*
  • Molecular Structure
  • Nicotinic Acids / chemistry
  • Nipecotic Acids / chemical synthesis*
  • Nipecotic Acids / chemistry
  • Nipecotic Acids / pharmacology
  • Proline* / analogs & derivatives*
  • Prosencephalon / metabolism
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Tiagabine
  • gamma-Aminobutyric Acid / metabolism


  • Anticonvulsants
  • GABA Antagonists
  • Nicotinic Acids
  • Nipecotic Acids
  • nipecotic acid
  • guvacine
  • gamma-Aminobutyric Acid
  • Proline
  • homoproline
  • Tiagabine