title: 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.affiliation: Department of Dental Anesthesiology and Special Care Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Jinzenji
authors.forename: Chiharu
authors.initials: C
authors.lastname: Sogawa
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyawaki
authors.forename: Xue-Fang
authors.initials: XF
authors.lastname: Wen
authors.forename: Dan
authors.initials: D
authors.lastname: Yi
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ohyama
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kitayama
authors.forename: Norio
authors.initials: N
authors.lastname: Sogawa
authors.forename: Katsuya
authors.initials: K
authors.lastname: Morita
mesh_terms: D000818:Animals; D001622:Betaine / Q000037:antagonists & inhibitors*; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D050485:GABA Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008815:Mice, Inbred Strains; D009437:Neuralgia / Q000188:drug therapy* / Q000235:genetics*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; C107429:NNC 05-2090; D010880:Piperidines; D001622:Betaine; D005680:gamma-Aminobutyric Acid