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

• Sodium current was partially blocked in a dose-dependent manner by antagonists of GABA plasma membrane transporters such as beta-alanine, nipecotic acid, 1-[2([(diphenylmethylene)imino]oxy)ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NO 711), and SKF89976-A at concentrations between 1 and 100 microm [16].

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].

References