NNC 711

GABA uptake blocker NNC-711 exhibits marked anticonvulsant action in two cortical epileptic models in immature rats.[Pubmed:10487180]

Epilepsia. 1999 Sep;40(9):1184-9.

PURPOSE: To study the anticonvulsant action of a gamma-aminobutyric acid (GABA) uptake inhibitor NNC-711 in two models of cortical epileptogenesis in immature rats. METHODS: Twelve-, 18-, and 25-day-old rat pups with implanted electrodes were used in this study. Epileptogenic foci were elicited by a local application of bicuculline methiodide (BMI) on the sensorimotor cortical region by means of an implanted cannula, and cortical epileptic afterdischarges (ADs) were induced by low-frequency stimulation (8 Hz) of the same cortical area. Epileptogenic foci were formed after pretreatment with NNC-711 (1 or 10 mg/kg, i.p.), and epileptic ADs were elicited in the second experimental series. Then NNC-711 was administered in the same doses, and stimulation was repeated. RESULTS: NNC-711 did not block the formation of epileptogenic foci, but it significantly suppressed the spontaneous transition of interictal focal into ictal activity in all age groups. The intensity of movements accompanying stimulation of the sensorimotor cortex was less under the influence of NNC-711 in the 18- and 25-day-old rats. The duration of cortical ADs was shortened in all age groups, but transient abolition of ADs was observed only after the higher dose in the 25-day-old rats. In addition, the intensity of clonic seizures appearing during ADs decreased, and the transition of ADs into another type due to an involvement of limbic structures failed to appear in the 18- and 25-day-old rats. CONCLUSIONS: Primary epileptogenesis in the cerebral cortex was hardly influenced by NNC-711, but the spread of epileptic activity was markedly suppressed. This effect was better expressed in the 18- and 25-day-old animals than in the youngest group.

Anti-ischemic and cognition-enhancing properties of NNC-711, a gamma-aminobutyric acid reuptake inhibitor.[Pubmed:11470258]

Eur J Pharmacol. 2001 Jul 13;424(1):37-44.

NNC-711 [1-(2-((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3-pyridinecarboxyli c acid hydrochloride], a gamma-aminobutyric acid (GABA) reuptake inhibitor with anticonvulsant activity, was investigated with respect to its cognition-enhancing and neuroprotective potency. 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. 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. In addition to a neuroprotective activity, NNC-711 exhibited significant cognition-enhancing actions. Daily administration of NNC-711, immediately prior to a spatial learning task, significantly reduced escape latencies in the water maze paradigm in both mature (postnatal day 80) and aged (28 months) rats. All of the above actions exhibited a bell-shaped response with an optimal dose of 0.5-1.0 mg/kg. These investigations with NNC-711 and previous clinical observations on the structurally related anticonvulsant tiagabine confirm the potential of GABA reuptake inhibitors as anti-amnesia and cognition-enhancing agents.

Effects of the GABA-uptake blocker NNC-711 on spontaneous sharp wave-ripple complexes in mouse hippocampal slices.[Pubmed:23460368]

Hippocampus. 2013 May;23(5):323-9.

The precise temporal and spatial activity patterns of neurons in cortical networks are organized by different state-dependent types of network oscillations. GABAergic inhibition plays a key role in the underlying mechanisms of such oscillations and it has been suggested that the duration of widely distributed phasic inhibitory postsynaptic potentials (IPSPs) determines the frequency of the resulting network oscillation. Here, we test this hypothesis in an in vitro model of sharp wave-ripple (SPW-R) complexes, a particularly fast pattern of network oscillations at approximately 200 Hz which is involved in memory consolidation. We recorded SPW-R in mouse hippocampal slices in the absence and presence of NCC-711, an inhibitor of GABA uptake. The resulting prolongation of IPSP resulted in reduced occurrence of SPW-R, whereas the superimposed fast oscillations as well as the precision of rhythmic cell synchronization remained stable. Application of Diazepam which is a positive modulator of the GABAA receptor led to consistent results. We conclude that phasic inhibition is a major regulator of network excitability in CA3 (where SPW-Rs are generated), but does not set the frequency of hippocampal ripples.

Effects of NNC 711, a GABA uptake inhibitor, on pentylenetetrazol-induced seizures in developing and adult rats.[Pubmed:9774221]

Naunyn Schmiedebergs Arch Pharmacol. 1998 Sep;358(3):334-41.

The anticonvulsant action of NNC 711 [(1-(2-((diphenylmethylene) amino) oxy) ethyl)-1,2,4,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride], an inhibitor of the GABA transporter GAT-1, was studied in a model of pentylenetetrazol-induced motor seizures in rats 7, 12, 18, 25, and 90 days old. NNC 711 at doses of 0.25-20 mg/kg i.p. exhibited two effects in rat pups: a suppression of minimal clonic seizures in age groups in which this type of seizure could be reliably elicited (i.e. in rats aged 18 and 25 days); and a specific suppression or restriction of the tonic phase of generalized tonic-clonic seizures (GTCS) expressed in 18- and especially 12-day-old rats. Effects of NNC 711 on GTCS in 7- and 25-day-old rats were irregular. Adult (i.e. 90-day-old) animals exhibited abolition of generalized tonic-clonic seizures; minimal clonic seizures were suppressed only after substantially higher doses. The abolition of minimal seizures by doses too low to influence generalized tonic-clonic seizures as observed in rat pups is unique among antiepileptic drugs. In addition, an EEG study in rat pups demonstrated dissociation of EEG signs and motor seizures in some animals.

Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1.[Pubmed:7851497]

Eur J Pharmacol. 1994 Oct 14;269(2):219-24.

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. The synaptic action of GABA is terminated by rapid uptake into presynaptic terminals and surrounding glial cells. Molecular cloning has revealed the existence of four distinct GABA transporters termed GAT-1, GAT-2, GAT-3, and BGT-1. Pharmacological inhibition of transport provides a mechanism for increasing GABA-ergic transmission, which may be useful in the treatment of various neuropsychiatric disorders. Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. These data suggest that the anticonvulsant activity of these compounds is mediated via inhibition of uptake by GAT-1.

NNC-711, a novel potent and selective gamma-aminobutyric acid uptake inhibitor: pharmacological characterization.[Pubmed:1468507]

Eur J Pharmacol. 1992 Dec 2;224(2-3):189-98.

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.