title: Synthesis of novel GABA uptake inhibitors. 3. Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents.
abstract: (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.
authors.affiliation: Health Care Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. L.Knutsen@Cerebrus.ltd.dk
authors.forename: L J
authors.initials: LJ
authors.lastname: Knutsen
authors.forename: K E
authors.initials: KE
authors.lastname: Andersen
authors.forename: J
authors.initials: J
authors.lastname: Lau
authors.forename: B F
authors.initials: BF
authors.lastname: Lundt
authors.forename: R F
authors.initials: RF
authors.lastname: Henry
authors.forename: H E
authors.initials: HE
authors.lastname: Morton
authors.forename: L
authors.initials: L
authors.lastname: Naerum
authors.forename: H
authors.initials: H
authors.lastname: Petersen
authors.forename: H
authors.initials: H
authors.lastname: Stephensen
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
authors.forename: C
authors.initials: C
authors.lastname: Thomsen
authors.forename: P O
authors.initials: PO
authors.lastname: Sørensen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D018360:Crystallography, X-Ray; D015195:Drug Design; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D018756:GABA Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D026901:Membrane Transport Proteins; D008958:Models, Molecular; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000737:chemistry* / Q000494:pharmacology; D009557:Nipecotic Acids / Q000737:chemistry* / Q000494:pharmacology; D027361:Organic Anion Transporters; D010091:Oximes / Q000138:chemical synthesis / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000927:Anticonvulsants; D002352:Carrier Proteins; D004987:Ethers; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009539:Nicotinic Acids; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; D010091:Oximes; C493415:Slc6a1 protein, rat; C030278:nipecotic acid; C015910:guvacine; D011392:Proline; C010983:homoproline