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

Fingerprint

GABA Plasma Membrane Transport Proteins
Neuralgia
CHO Cells
gamma-Aminobutyric Acid
Inhibitory Concentration 50
Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Sciatic Nerve
Intravenous Administration
Ligation
Spinal Cord
Animal Models
betaine plasma membrane transport proteins

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

Antiallodynic action of 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2- methyoxyphenyl)-4-piperidinol (NNC05-2090), a betaine/GABA transporter inhibitor. / Jinzenji, Ayako; Sogawa, Chiharu; Miyawaki, Takuya; Wen, Xue Fang; Yi, Dan; Ohyama, Kazumi; Kitayama, Shigeo; Sogawa, Norio; Morita, Katsuya.

In: Journal of Pharmacological Sciences, Vol. 125, No. 2, 2014, p. 217-226.

Research output: Contribution to journalArticle

Jinzenji, Ayako ; Sogawa, Chiharu ; Miyawaki, Takuya ; Wen, Xue Fang ; Yi, Dan ; Ohyama, Kazumi ; Kitayama, Shigeo ; Sogawa, Norio ; Morita, Katsuya. / Antiallodynic action of 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2- methyoxyphenyl)-4-piperidinol (NNC05-2090), a betaine/GABA transporter inhibitor. In: Journal of Pharmacological Sciences. 2014 ; Vol. 125, No. 2. pp. 217-226.
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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.",
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AU - Jinzenji, Ayako

AU - Sogawa, Chiharu

AU - Miyawaki, Takuya

AU - Wen, Xue Fang

AU - Yi, Dan

AU - Ohyama, Kazumi

AU - Kitayama, Shigeo

AU - Sogawa, Norio

AU - Morita, Katsuya

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