title: NNC-711, a novel potent and selective gamma-aminobutyric acid uptake inhibitor: pharmacological characterization.
abstract: NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride) is a novel, potent and selective gamma-aminobutyric acid (GABA) uptake inhibitor. NNC-711 inhibited synaptosomal (IC50 = 47 nM), neuronal (IC50 = 1238 nM) and glial (IC50 = 636 nM) GABA uptake in vitro NNC-711 lacked affinity for other neurotransmitter receptor binding sites, uptake sites and ion channels examined in vitro. In vivo, NNC-711 was a potent anticonvulsant compound against rodent seizures induced by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (ED50 (clonic) = 1.2 mg/kg i.p.), pentylenetetrazole (PTZ) (ED50 (tonic) = 0.72 mg/kg i.p., mouse; and ED50 (tonic) = 1.7 mg/kg, rat), or audiogenic (ED50 (clonic and tonic) = 0.23 mg/kg i.p.). At higher doses NNC-711 produced behavioral side effects characterized by inhibition of traction (ED50 = 23 mg/kg i.p.), rotarod (ED50 = 10 mg/kg i.p.) and exploratory locomotor activity (ED50 = 45 mg/kg i.p.) in the mouse. Following acute (3-h) in vivo pretreatment with NNC-711, behavioral tolerance developed to its motor impairing side effects (inhibition of traction, rotarod or exploratory locomotor activity) without corresponding tolerance to the anticonvulsant effects. These data suggest that NNC-711 will be useful for future in vitro and in vivo experiments to elucidate the role of the GABA uptake carrier in the central nervous system.
authors: Novo Nordisk A/S, Department of Receptor Neurochemistry, Måløv, Denmark.
authors: P D
authors: PD
authors: Suzdak
authors: K
authors: K
authors: Frederiksen
authors: K E
authors: KE
authors: Andersen
authors: P O
authors: PO
authors: Sørensen
authors: L J
authors: LJ
authors: Knutsen
authors: E B
authors: EB
authors: Nielsen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002243:Carbolines; D002478:Cells, Cultured; D003292:Convulsants; D005260:Female; D018756:GABA Antagonists; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D010433:Pentylenetetrazole; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D002243:Carbolines; D003292:Convulsants; D018756:GABA Antagonists; D009539:Nicotinic Acids; D009557:Nipecotic Acids; D010091:Oximes; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; C078793:NNC 711; D005680:gamma-Aminobutyric Acid; C035874:FG 7142; D010433:Pentylenetetrazole; D000078308:Tiagabine