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Anticonvulsant properties of two GABA uptake inhibitors NNC 05-2045 and NNC 05-2090, not acting preferentially on GAT-1.

Abstract
Two novel nipecotic acid derivatives, 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(4-methoxyphenyl)-4-piperidino l (NNC 05-2045) and 1-(3-(9H-Carbazol-9-yl)-l-propyl)-4-(2-methoxyphenyl)-4-piperidino l (NNC 05-2090) have been tested for inhibition of gamma-amino butyric acid (GABA) transporters in synaptosomal preparations of rat cerebral cortex and inferior colliculus and found to differ markedly from gabitril (tiagabine), a selective GAT-1 inhibitor. IC50 values for inhibition of [3H]GABA uptake into synaptosomes from cerebral cortex for NNC 05-2045 and NNC 05-2090 were 12 +/- 2 and 4.4 +/- 0.8 microM, respectively. In synaptosomes from inferior colliculus in the presence of 1 microM 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid (NNC 05-0711), a highly potent and selective GAT-1 inhibitor, IC50 values for inhibition of [3H]GABA uptake were 1.0 +/- 0.1 and 2.5 +/- 0.7 microM, respectively. A receptor profile showed that NNC 05-2045 has binding affinities to sigma-, alpha 1- and D2-receptors of 113, 550 and 122 nM, respectively. NNC 05-2090 displayed alpha 1- and D2-receptor affinity of 266 and 1632 nM, respectively. The anticonvulsant action of both compounds was tested in four rodent models after intra peritoneal (i.p.) injection. Both NNC 05-2090 dose-dependently inhibited sound-induced tonic and clonic convulsions in DBA/2 mice with ED50 values of 6 and 19 mumol/kg, respectively. NNC 05-2045 also antagonized sound-induced seizures in genetic epilepsy prone rats (GEP rats) with ED50 values against wild running, clonic and tonic convulsions of 33, 39 and 39 mumol/kg, respectively (NNC 05-2090 was not tested in GEP rats). Both NNC 05-2045 and NNC 05-2090 dose-dependently antagonized tonic hindlimb extension in the maximal electroshock (MES) test with ED50 values of 29 and 73 mumol/kg, respectively. In amygdala kindled rats NNC 05-2045 and NNC 05-2090 significantly (P < 0.05) reduced generalized seizure severity (seizure grade 3-5) at highest doses (72-242 mumol/kg) and NNC 05-2090 also significantly reduced afterdischarge duration at these doses (P < 0.05). These data show that inhibition of GABA uptake through non-GAT-1 transporters has different anticonvulsant effects than selective GAT-1 inhibitors (e.g. tiagabine) in that enhanced efficacy against MES and reduced efficacy against kindled seizures is observed. Although a contribution of adrenergic agonistic effects cannot be entirely ruled out, it is proposed that inhibition of GAT-3 (mouse GAT4) is primarily responsible for the anticonvulsant action of these two nipecotic acid derivatives in MES, amygdala kindled rats and in sound-induced seizures in GEP-rats and DBA/2 mice.
AuthorsN O Dalby, C Thomsen, A Fink-Jensen, J Lundbeck, B Søkilde, C M Man, P O Sørensen, B Meldrum
JournalEpilepsy research (Epilepsy Res) Vol. 28 Issue 1 Pg. 51-61 (Jul 1997) ISSN: 0920-1211 [Print] Netherlands
PMID9255599 (Publication Type: Journal Article)
Chemical References
  • Anticonvulsants
  • Carbazoles
  • Carrier Proteins
  • GABA Plasma Membrane Transport Proteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • NNC 05-2045
  • NNC 05-2090
  • Neurotransmitter Uptake Inhibitors
  • Organic Anion Transporters
  • Piperidines
  • Slc6a1 protein, mouse
  • Slc6a1 protein, rat
  • Slc6a11 protein, mouse
  • Slc6a13 protein, mouse
  • gamma-Aminobutyric Acid
Topics
  • Animals
  • Anticonvulsants (pharmacology)
  • Carbazoles (pharmacology)
  • Carrier Proteins (drug effects)
  • Cerebral Cortex (drug effects)
  • Dose-Response Relationship, Drug
  • Female
  • GABA Plasma Membrane Transport Proteins
  • Male
  • Membrane Proteins (drug effects)
  • Membrane Transport Proteins
  • Mice
  • Neurotransmitter Uptake Inhibitors (pharmacology)
  • Organic Anion Transporters
  • Piperidines (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • gamma-Aminobutyric Acid (pharmacology)

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