sk&f-89976-a has been researched along with nipecotic-acid* in 2 studies
2 other study(ies) available for sk&f-89976-a and nipecotic-acid
| Article | Year |
|---|---|
Synthesis of novel GABA uptake inhibitors. 3. Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents.
(3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid 1 (tiagabine, Gabitril) is a potent and selective gamma-aminobutyric acid (GABA) uptake inhibitor with proven anticonvulsant efficacy in humans. This drug, which has a unique mechanism of action among marketed anticonvulsant agents, has been launched for add-on treatment of partial seizures with or without secondary generalization in patients >12 years of age. Using this new agent as a benchmark, we have designed two series of novel GABA uptake inhibitors of remarkable potency, using a putative new model of ligand interaction at the GABA transporter type 1 (GAT-1) uptake site. This model involves the postulated interaction of an electronegative region in the GABA uptake inhibitor with a positively charged domain in the protein structure of the GAT-1 site. These two novel series of anticonvulsant agents contain diaryloxime or diarylvinyl ether functionalities linked to cyclic amino acid moieties and were derived utilizing the new model, via a series of design steps from the known 4,4-diarylbutenyl GABA uptake inhibitors. The new compounds are potent inhibitors of [(3)H]-GABA uptake in rat brain synaptosomes in vitro, and their antiepileptic potential was demonstrated in vivo by their ability to protect against seizures induced by the benzodiazepine receptor inverse agonist methyl 4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate (DMCM) in mice. From structure-activity studies of these new GABA uptake inhibitors, we have shown that insertion of an ether oxygen in conjugation with the double bond in tiagabine (K(i) = 67 nM) improves in vitro potency by 5-fold to 14 nM. Topics: Animals; Anticonvulsants; Carrier Proteins; Crystallography, X-Ray; Drug Design; Ethers; GABA Antagonists; GABA Plasma Membrane Transport Proteins; Membrane Proteins; Membrane Transport Proteins; Models, Molecular; Molecular Structure; Nicotinic Acids; Nipecotic Acids; Organic Anion Transporters; Oximes; Proline; Rats; Structure-Activity Relationship; Synaptic Transmission | 1999 |
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 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. Topics: Animals; Anticonvulsants; GABA Antagonists; gamma-Aminobutyric Acid; Molecular Structure; Nicotinic Acids; Nipecotic Acids; Proline; Prosencephalon; Rats; Stereoisomerism; Structure-Activity Relationship; Synaptosomes; Tiagabine | 1993 |