Anticonvulsant properties of two GABA uptake inhibitors NNC 05-2045 and NNC 05-2090, not acting preferentially on GAT-1.
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.
Dalby
N O
NO
Novo Nordisk, Måløv, Denmark. nod@novo.dk
Thomsen
C
C
Fink-Jensen
A
A
Lundbeck
J
J
Søkilde
B
B
Man
C M
CM
Sørensen
P O
PO
Meldrum
B
B
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects*; D026901:Membrane Transport Proteins; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D027361:Organic Anion Transporters; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000927:Anticonvulsants; D002227:Carbazoles; D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D027361:Organic Anion Transporters; D010880:Piperidines; D005680:gamma-Aminobutyric Acid; C108938:NNC 05-2045; C107429:NNC 05-2090; C493414:Slc6a1 protein, mouse; C493415:Slc6a1 protein, rat; C493419:Slc6a13 protein, mouse; C079264:Slc6a11 protein, mouse