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-buteny] acid 1(tiagabine, Gabitril) i s a potent and selective gamma-aminobutyric acid (GABA) uptake inhibitor wi th 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 general ization 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 trans porter type 1 (GAT-1) uptake site. This model involves the postulated inter action of an electronegative region in the CABA uptake inhibitor with a pos itively charged domain in the protein structure of the GAT-1 site. These tw o 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-d iarylbutenyl GABA uptake inhibitors. The new compounds are potent inhibitor s of [H-3]-GABA uptake in rat brain synaptosomes in vitro, and their antiep ileptic potential was demonstrated in vivo by their ability to protect agai nst seizures induced by the benzodiazepine receptor inverse agonist methyl 4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate (DMCM) in mice. From str ucture-activity studies of these new GABA uptake inhibitors, we have shown that insertion of an ether oxygen in conjugation with the double bond in ti agabine (K-i = 67 nM) improves in vitro potency by 5-fold to 14 nM.