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

Ayako Jinzenji, Chiharu Sogawa, Takuya Miyawaki, Xue Fang Wen, Dan Yi, Kazumi Ohyama, Shigeo Kitayama, Norio Sogawa, Katsuya Morita

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)217-226
Number of pages10
JournalJournal of Pharmacological Sciences
Volume125
Issue number2
DOIs
Publication statusPublished - 2014

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Keywords

  • Antiallodynic action
  • Betaine/GABA transporter
  • Monoamine transporter
  • Neuropathic pain
  • NNC05-2090

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

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