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Chemical Compound Review

Nnc-711     1-[2-(benzhydrylideneamino) oxyethyl]-5,6...

Synonyms: CHEMBL545050, N142_SIGMA, NO-711, NNC 711, N-142, ...
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Disease relevance of Nnc-711

  • High doses of NNC-711 (207-310 mumol kg-1) and of (+/-)-nipecotic acid (39-78 mmol kg-1) induced ataxia and myoclonic seizures 0.25-1 h [1].
  • NO-711 also shifted the intensity-response relationship of the ganglion cell, reducing its sensitivity to light [2].

Psychiatry related information on Nnc-711

  • Perfusion with the potent GABA re-uptake inhibitor NNC-711, for 60 min prior to administration of maximal electroshock, increased GABA levels (436 +/- 58%) and abolished the seizure-induced decrease [3].
  • In the rat, administration of NNC-711 immediately prior to training prevented amnesia for a passive avoidance task induced by the acetylcholine receptor antagonist scopolamine [4].
  • 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 [5].

High impact information on Nnc-711

  • The most potent inhibitors of the cloned human GAT-1 are NNC-711 (IC50 = 0.04 mM) and tiagabine (IC50 = 0.07 mM) [6].
  • Distinct sensitivity to NO-711 was shown to be characteristic for different steps of alpha-latrotoxin-stimulated [3H]GABA release from the control, untreated synaptosomes: lack of any effect of NO-711 during the first 2 min and powerful inhibition in 10 min after the toxin application [7].
  • CONCLUSIONS: Primary epileptogenesis in the cerebral cortex was hardly influenced by NNC-711, but the spread of epileptic activity was markedly suppressed [8].
  • However, enhancement of local GABA concentration by perfusion of a GABA uptake inhibitor (NO-711) revealed an action of endogenous GABA at these presynaptic GABAB receptors [9].
  • R(-)N-(4,4-di(3-methylthien-2-yl)-but-3-enyl) nipecotic acid hydrochloride (tiagabine, 5-20 mg/kg i.p.) and 1-[2-[[(diphenylmethylene) imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711, 1-10 mg/kg i.p.) significantly reduced the severity of dystonia [10].

Biological context of Nnc-711

  • In whole-mount retinas, NO-711, bicuculline, I4AA, or picrotoxin hyperpolarized the HCs and enhanced the light responses under dark-adapted conditions, and blocked the time-dependent recovery of HC membrane potential and light responses during background illumination [11].
  • GABA transport inhibitors (tiagabine and NO-711) prolonged evoked IPSC decay kinetics of control CA1 pyramidal cells (or normotopic cells) but had no effect on heterotopic neurons [12].

Anatomical context of Nnc-711

  • NNC-711 was also effective in protecting against ischemia-induced death of CA1 pyramidal neurons in a model of bilateral common carotid artery occlusion in the gerbil [4].
  • 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 [5].
  • In cultures containing O-2A progenitor cells and Type 2 astrocytes, approximately 75% of GABA uptake is sensitive to NNC-711 and drug potencies at this site correlate well with their potencies at GAT-1; GAT-1 mRNA is abundant [13].
  • MF responses were potentiated by blocking the plasma membrane GABA transporter GAT-1 with NO-711 or by allosterically modulating GABAA receptors with flurazepam [14].
  • Furthermore, we find that the amount of GABA(C) receptor-mediated reciprocal feedback between bipolar cell terminals and amacrine cells is greatly increased when GAT-1 transporters are specifically blocked by NO-711 (1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride) [15].

Associations of Nnc-711 with other chemical compounds


Gene context of Nnc-711

  • Drug potencies at the NNC-711-resistant component correlate well with their potencies at GAT-2 and GAT-3; mRNAs for both of these transporters are present (though GAT-2 mRNA is the more abundant), as is BGT-1 mRNA [13].

Analytical, diagnostic and therapeutic context of Nnc-711

  • (a) "Slow" charge movements, which require extracellular Na+ and probably reflect occlusion of Na+ by GAT1, were defined in three ways with similar results: by application of the high-affinity GAT1 blocker (NO-711), by application of a high concentration (120 mM) of cytoplasmic Cl-, and by removal of extracellular Na+ via pipette perfusion [17].
  • In neuronal cultures approximately 70% of GABA transport is sensitive to the GAT-1-selective ligand NNC-711 and drug potencies at this site correlate well with their potencies at GAT-1; GAT-1 mRNA is abundant in these cultures as determined by northern blot analysis [13].


  1. The gamma-aminobutyric acid uptake inhibitor, tiagabine, is anticonvulsant in two animal models of reflex epilepsy. Smith, S.E., Parvez, N.S., Chapman, A.G., Meldrum, B.S. Eur. J. Pharmacol. (1995) [Pubmed]
  2. GABA transporters regulate inhibition in the retina by limiting GABA(C) receptor activation. Ichinose, T., Lukasiewicz, P.D. J. Neurosci. (2002) [Pubmed]
  3. Decreased GABA release following tonic-clonic seizures is associated with an increase in extracellular glutamate in rat hippocampus in vivo. Rowley, H.L., Martin, K.F., Marsden, C.A. Neuroscience (1995) [Pubmed]
  4. Anti-ischemic and cognition-enhancing properties of NNC-711, a gamma-aminobutyric acid reuptake inhibitor. O'Connell, A.W., Fox, G.B., Kjøller, C., Gallagher, H.C., Murphy, K.J., Kelly, J., Regan, C.M. Eur. J. Pharmacol. (2001) [Pubmed]
  5. NNC-711, a novel potent and selective gamma-aminobutyric acid uptake inhibitor: pharmacological characterization. Suzdak, P.D., Frederiksen, K., Andersen, K.E., Sørensen, P.O., Knutsen, L.J., Nielsen, E.B. Eur. J. Pharmacol. (1992) [Pubmed]
  6. The GABA transporter and its inhibitors. Soudijn, W., van Wijngaarden, I. Current medicinal chemistry. (2000) [Pubmed]
  7. Involvement of membrane GABA transporter in alpha-latrotoxin-stimulated [3H]GABA release. Linetska, M.V., Storchak, L.G., Tarasenko, A.S., Himmelreich, N.H. Neurochem. Int. (2004) [Pubmed]
  8. GABA uptake blocker NNC-711 exhibits marked anticonvulsant action in two cortical epileptic models in immature rats. Bernásková, K., Slamberová, R., Mares, P. Epilepsia (1999) [Pubmed]
  9. Activation of presynaptic GABAB receptors inhibits evoked IPSCs in rat magnocellular neurons in vitro. Mouginot, D., Kombian, S.B., Pittman, Q.J. J. Neurophysiol. (1998) [Pubmed]
  10. Antidystonic efficacy of gamma-aminobutyric acid uptake inhibitors in the dtsz mutant. Kreil, A., Richter, A. Eur. J. Pharmacol. (2005) [Pubmed]
  11. Modulation of horizontal cell function by GABA(A) and GABA(C) receptors in dark- and light-adapted tiger salamander retina. Yang, X.L., Gao, F., Wu, S.M. Vis. Neurosci. (1999) [Pubmed]
  12. Heterotopic neurons with altered inhibitory synaptic function in an animal model of malformation-associated epilepsy. Calcagnotto, M.E., Paredes, M.F., Baraban, S.C. J. Neurosci. (2002) [Pubmed]
  13. Re-evaluation of GABA transport in neuronal and glial cell cultures: correlation of pharmacology and mRNA localization. Borden, L.A., Smith, K.E., Vaysse, P.J., Gustafson, E.L., Weinshank, R.L., Branchek, T.A. Recept. Channels (1995) [Pubmed]
  14. GABAergic signaling at mossy fiber synapses in neonatal rat hippocampus. Safiulina, V.F., Fattorini, G., Conti, F., Cherubini, E. J. Neurosci. (2006) [Pubmed]
  15. GABA transporters regulate a standing GABAC receptor-mediated current at a retinal presynaptic terminal. Hull, C., Li, G.L., von Gersdorff, H. J. Neurosci. (2006) [Pubmed]
  16. Expression and functional characterization of GABA transporters in crayfish neurosecretory cells. Garduño, J., Elenes, S., Cebada, J., Becerra, E., García, U. J. Neurosci. (2002) [Pubmed]
  17. GAT1 (GABA:Na+:Cl-) cotransport function. Kinetic studies in giant Xenopus oocyte membrane patches. Lu, C.C., Hilgemann, D.W. J. Gen. Physiol. (1999) [Pubmed]
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