ANTICONVULSANT PROPERTIES OF 2 GABA UPTAKE INHIBITORS NNC-05-2045 ANDNNC-05-2090, NOT ACTING PREFERENTIALY ON GAT-1

Two novel nipecotic acid derivatives, -9-yl)-1-propyl)-4-(4-methoxyphe npl)-4-piperidinol (NNC 05-2045) and -9-yl)-1-propyl)-4-(2-methoxyphen yl)-4-piperidinol (NNC 05-2090) have been tested for inhibition of gam ma-amino butyric acid (GABA) transporters in synaptosomal preparations of rat cerebral cortex and inferior colliculus and found to differ ma rkedly from gabitril(R) (tiagabine), a selective GAT-1 inhibitor. IC50 values for inhibition of [H-3]GABA uptake into synaptosomes from cere bral cortex for NNC 05-2045 and NNC 05-2090 were 12+/-2 and 4.4+/-0.8 mu M, respectively. In synaptosomes from inferior colliculus in the pr esence of 1 mu M oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic ac id (NNC 05-0711), a highly potent acid (NNC 05-0711), a highly potent and selective GAT-1 inhibitor, IC50 values for inhibition of [H-3]GABA uptake were 1.0+/-0.1 and 2.5+/-0.7 mu M, respectively. A receptor pr ofile showed that NNC 05-2045 has binding affinities to sigma-, alpha( 1)- and D-2-receptors of 113, 550 and 122 nM, respectively. NNC 05-209 0 displayed alpha(1)- and D-2-receptor affinity of 266 and 1632 nM, re spectively. The anticonvulsant action of both compounds was tested in four rodent models after intra peritoneal (i.p.) injection. Both NNC 0 5-2045 and NNC 05-2090 dose-dependently inhibited sound-induced tonic and clonic conclusions in DBA/2 mice with ED50 values of 6 and 19 mu m ol/kg, respectively. NNC 05-2045 also antagonized sound-induced seizur es in genetic epilepsy prone rats (GEP rats) with ED50 values against wild running, clonic and tonic convulsions of 33, 39 and 39 mu mol/kg, respectively (NNC 05-2090 was not tested in GEP rats). Both NNC 05-20 45 and NNC 05-2090 dose-dependently antagonized tonic hindlimb extensi on in the maximal electroshock (MES) test with ED50 values of 29 and 7 3 mu mol/kg, respectively, In amygdala kindled rats NNC 05-2045 and NN C 05-2090 significantly (P < 0.05) reduced generalized seizure severit y (seizure grade 3-5) at highest doses (72-242 mu mol/kg) and NNC 05-2 090 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 selectiv e GAT-1 inhibitors (e.g. tiagabine) in that enhanced efficacy) against MES and reduced efficacy against kindled seizures is observed. Althou gh a contribution of adrenergic agonistic effects cannot be entirely r uled out. it is proposed that inhibition of GAT-3 (mouse GAT4) is prim arily responsible for the anticonvulsant action of these two nipecotic acid derivatives in MES. amygdala kindled rats and in sound-induced s eizures in GEP-rats and DBA/2 mice. (C) 1997 Elsevier Science B.V.