Antiallodynic action of 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), a betaine/GABA transporter inhibitor.

Abstract

The GABAergic system in the spinal cord has been shown to participate in neuropathic pain in various animal models. GABA transporters (GATs) play a role in controlling the synaptic clearance of GABA; however, their role in neuropathic pain remains unclear. In the present study, we compared the betaine/GABA transporter (BGT-1) with other GAT subtypes to determine its participation in neuropathic pain using a mouse model of sciatic nerve ligation. 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), an inhibitor that displays moderate selectivity for BGT-1, had an antiallodynic action on model mice treated through both intrathecally and intravenous administration routes. On the other hand, SKF89976A, a selective GAT-1 inhibitor, had a weak antiallodynic action, and (S)-SNAP5114, an inhibitor that displays selectivity for GAT-3, had no antiallodynic action. Systemic analysis of these compounds on GABA uptake in CHO cells stably expressing BGT-1 revealed that NNC05-2090 not only inhibited BGT-1, but also serotonin, noradrenaline, and dopamine transporters, using a substrate uptake assay in CHO cells stably expressing each transporter, with IC50: 5.29, 7.91, and 4.08 μM, respectively. These values were similar to the IC50 value at BGT-1 (10.6 μM). These results suggest that the antiallodynic action of NNC05-2090 is due to the inhibition of both BGT-1 and monoamine transporters.

• Authors: Ayako Jinzenji, Chiharu Sogawa, Takuya Miyawaki, Xue-Fang Wen, Dan Yi, Kazumi Ohyama, Shigeo Kitayama, Norio Sogawa, Katsuya Morita
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 125 Issue 2 Pg. 217-26 ( 2014) ISSN: 1347-8648 [Electronic] Japan
• PMID: 24881960 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GABA Plasma Membrane Transport Proteins
• NNC 05-2090
• Piperidines
• Betaine
• gamma-Aminobutyric Acid

Topics

• Animals
• Betaine (antagonists & inhibitors)
• CHO Cells
• Cricetulus
• Disease Models, Animal
• Dose-Response Relationship, Drug
• GABA Plasma Membrane Transport Proteins (drug effects, physiology)
• Male
• Mice, Inbred Strains
• Neuralgia (drug therapy, genetics)
• Piperidines (administration & dosage, pharmacology, therapeutic use)
• gamma-Aminobutyric Acid (metabolism)