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 [3H]-GABA upt...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1993-06, Vol.36 (12), p.1716-1725
Main Authors: Andersen, Knud Erik, Braestrup, Claus, Groenwald, Frederik C, Joergensen, Anker S, Nielsen, Erik B, Sonnewald, Ursula, Soerensen, Per O, Suzdak, Peter D, Knutsen, Lars J. S
Format: Article
Language:English
Subjects:
Animals
Anticonvulsants - chemical synthesis
Anticonvulsants - chemistry
Anticonvulsants - pharmacology
GABA Antagonists
gamma-Aminobutyric Acid - metabolism
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00064a005