title: Characterization of tiagabine (NO-328), a new potent and selective GABA uptake inhibitor.
abstract: Tiagabine (NO-328) (R(-)-N-[4,4-bis(3-methylthien-2-yl)but-3-enyl]nipecotic acid, hydrochloride) is a new centrally acting GABA uptake inhibitor. The anticonvulsant activity of tiagabine was evaluated against seizures induced by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), pentylenetetrazol, bicuculline, maximal electrostimulation (MES), or high intensity sound. The sedative actions of tiagabine were evaluated in tests for traction, rotarod performance and exploratory behavior. Finally, interoceptive properties of tiagabine were assessed using diazepam-, CGS 9896-, pentylenetetrazol-, or amphetamine-discriminating rats. Tiagabine was an effective anticonvulsant in doses which did not produce sedation or motor debilitation, although it was not potent against MES. In a manner similar to other anti-epileptic drugs, tiagabine potentiated dopaminergic function (methylphenidate-induced gnawing in mice) although it did not substitute for amphetamine in amphetamine-trained animals. Furthermore, although tiagabine antagonized DMCM-induced convulsions, it exhibited neither CGS 9896 or diazepam-like interoceptive effects, nor did it block (or potentiate) pentylenetetrazol-discrimination. Thus, GABA uptake inhibition represents a novel rationale for a valproate-like anticonvulsant drug therapy.
authors.affiliation: Laboratory of Behavioral Pharmacology, Novo Nordisk A/S, Bagsvaerd, Denmark.
authors.forename: E B
authors.initials: EB
authors.lastname: Nielsen
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
authors.forename: K E
authors.initials: KE
authors.lastname: Andersen
authors.forename: L J
authors.initials: LJ
authors.lastname: Knutsen
authors.forename: U
authors.initials: U
authors.lastname: Sonnewald
authors.forename: C
authors.initials: C
authors.lastname: Braestrup
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002243:Carbolines / Q000037:antagonists & inhibitors; D002998:Clonazepam / Q000494:pharmacology; D003292:Convulsants / Q000037:antagonists & inhibitors; D003975:Diazepam / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D014179:Neurotransmitter Uptake Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D009539:Nicotinic Acids / Q000494:pharmacology; D009557:Nipecotic Acids / Q000009:adverse effects / Q000494:pharmacology*; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D002243:Carbolines; D003292:Convulsants; D018756:GABA Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D009539:Nicotinic Acids; D009557:Nipecotic Acids; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; C045597:SK&F 100330-A; D003975:Diazepam; D010433:Pentylenetetrazole; D000078308:Tiagabine