NNC-711, a novel potent and selective γ-aminobutyric acid uptake inhibitor: pharmacological characterization

Abstract

NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloridc) is a novel, potent and selective γ-aminobutyric acid (GABA) uptake inhibitor. NNC-711 inhibited synaptosomal (IC 50 = 47 nM), neuronal (IC 50 = 1238 nM) and glial (IC 50 = 636 nM) GABA uptake in vitro NNC-711 lacked affinity for other neurotransmitter rece binding sites, uptake sites and ion channels examined in vitro. In vivo, NNC-711 was a potent anticonvulsunt compound against rodent seizures induced by methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) (ED 50 (clonie) = 1.2 mg/kg i.p.), pentylenetetrazole (PTZ) (ED 50 (tonic) = 0.72 mg/kg i.p., mouse; and ED 50 (tonic) = 1.7 mg/kg, rat), or audiogenic (ED 50 (clonic and tonic) = 0.23 mg/kg i.p.),. At higher doses NNC-711 produced behavioral side effects characterized by inhibition of traction (ED 50 = 23 mg/kg i.p.), rotarod (ED 50 = 10 mg/kg i.p,) and exploratory locomotor activity (ED 50 = 45 mg/kg i.p.) in the mouse. Following acute (3-h) in vivo pretrcatmcnt with NNC-711, behavioral tolerance developed to its motor imparing 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.