In this study azetidine derivatives representing conformationally constrained GABA or beta-alanine analogs were evaluated for their potency as GABA-uptake inhibitors. The study comprised derivatives substituted in 2- as well as in 3-position with either an acetic acid moiety or a carboxylic acid function. In addition, azetidine derivatives bearing a tetrazole ring as a bioisosteric substitute for a carboxylic acid group were included. 3-Hydroxy-3-(4-methoxyphenyl)azetidine derivatives were explored as analogs of the known GABA-uptake inhibitor NNC-05-2045 exhibiting an azetidine ring instead of a piperidine ring present in the latter. Both, N-unsubstituted compounds as well as their N-alkylated lipophilic derivatives, were biologically evaluated for their affinity to the GAT-1 and GAT-3 transporters. Azetidin-2-ylacetic acid derivatives provided with a 4,4-diphenylbutenyl or 4,4-bis(3-methyl-2-thienyl)butenyl moiety as lipophilic residue were found to exhibit the highest potency at GAT-1 with IC50 values of 2.83+/-0.67 microM and 2.01+/-0.77 microM, respectively. The most potent GAT-3 inhibitor among these compounds appeared to be the beta-alanine analog 1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}azetidine-3-carboxylic acid (12d) displaying an IC50 value of 15.3+/-4.5 microM. Whereas the tetrazole derivatives showed no potency as GABA-uptake inhibitors, the 3-hydroxy-3-(4-methoxyphenyl)azetidine derivatives exhibited moderate affinity to GAT-1 (compound 18b: IC50=26.6+/-3.3 microM) and to GAT-3 (compound 18e: IC50=31.0+/-4.7 microM).

01 Nov 2000·NeuropharmacologyQ2 · MEDICINE

GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors

Q2 · MEDICINE

Article

Author: Dalby, N O

The present study examines the effect of tiagabine (a selective inhibitor of GABA transporter 1, GAT-1), SNAP-5114 (a semi-selective inhibitor of rat GAT-3/mouse GAT4) and NNC 05-2045 (a non-selective GABA uptake inhibitor) in modulating GABA levels in the hippocampus and thalamus. Anticonvulsant effects of the same compounds were assessed (after intranigral administration) after maximal electroshock (MES) in juvenile rats. Anticonvulsant effects were also tested after intraperitoneal (i.p.) administration against audiogenic seizures in DBA/2 mice and against pentylentetrazole (PTZ)-induced tonic convulsions or MES in NMRI mice. Tiagabine (30 microM, perfused through the microdialysis probe in halothane anaesthetized rats) increased GABA levels to (% basal+/-SEM) 645+/-69 in the hippocampus and 409+/-61 in the thalamus. SNAP-5114 (100 microM) increased GABA levels in the thalamus (% basal+/-SEM) to 247+/-27 but had no effect on hippocampal GABA-levels. NNC 05-2045 (100 microM) increased GABA levels both in the hippocampus (% basal+/-SEM, 251+/-51) and in the thalamus (298+/-27). All compounds protected against tonic hindlimb extension (THE) in juvenile male rats after intranigral administration. Sound induced convulsions in DBA/2 mice were dose-dependently inhibited by all compounds (administered intraperitoneal, i.p.) with ED(50) values of 1, 6 and 110 micromol/kg, for tiagabine, NNC 05-2045 and SNAP-5114, respectively. Tiagabine and NNC 05-2045 but not SNAP-5114 protected against PTZ-induced tonic convulsions whereas only NNC 05-2045 protected against MES-induced tonic convulsions in NMRI mice. However, tiagabine and NNC 05-2045 exerted a synergistic effect in the MES model. These findings substantiate and extend previous findings of different effects of selective versus non-selective GABA uptake inhibitors in animal models of epilepsy.

01 Jul 1997·Epilepsy ResearchQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Nils Ole Dalby ; Jane Lundbeck ; Brian Meldrum ; Christian Thomsen ; Per Olaf Sørensen ; Chiu Ming Man ; Anders Fink-Jensen ; Birgitte Søkilde

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Epilepsy	Preclinical	DK	Novo Nordisk A/S	01 Jul 1997

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