Antiallodynic Action of 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), a Betaine/GABA Transporter Inhibitor

Abstract

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 IC 50 : 5.29, 7.91, and 4.08 mM, respectively. These values were similar to the IC 50 value at BGT-1 (10.6 mM). These results suggest that the antiallodynic action of NNC05-2090 is due to the inhibition of both BGT-1 and monoamine transporters.

Osmoregulatory Role of Betaine and Betaine/γ-Aminobutyric Acid Transporter 1 in Post-Traumatic Syringomyelia

“…In the literature, NNC 05-2090 inhibited GABA transport through BGT1 in vitro as well as in a mouse model when injected using both intrathecal and intravenous administration. 52 In another study, NNC 05-2090 showed inhibitory activity to abrogate betaine transport through BGT1 to counteract the protective role of betaine in cognitive development in the Alzheimer's disease animal model. 53 Next, we utilized NNC 05-2090 to investigate the effects of inhibiting betaine transport on cell size regulation over time when exposed to hypertonic media using our cell size regulation assay (Figure 6B).…”

MS Binding Assays for the Three Monoamine Transporters Using the Triple Reuptake Inhibitor (1R,3S)‐Indatraline as Native Marker

“…was published that also compared the uptake inhibition of compound 22 at monoamine and GATs. Also according to their results, 22 shows higher inhibitory potencies at DAT (pIC 50 : 5.4), NET (pIC 50 : 5.1), and SERT (pIC 50 : 5.3) in [ 3 H]DA, [ 3 H]NE, and [ 3 H]5‐HT transport assays (based on CHO cells stably expressing the corresponding rat monoamine transporters) as compared with the inhibitory potencies at the four GAT subtypes in [ 3 H]GABA transport assays [based on murine transporters stably expressed in CHO cells, pIC 50 values: 4.5 (GAT‐1), 4.3 (GAT‐2), 4.6 (GAT‐3), and 5.0 (BGT‐1)] 19…”

Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

“…Intrathecal administration of NO-711 produced antiallodynic activities rats with CCI-induced neuropathic pain and in rats with PINP (Li et al, 2011; Yadav et al, 2015). On the other hand, intraperitoneal administration of another GAT-1 inhibitor SKF89976A did not have effect on established allodynia in a partial sciatic nerve ligation (PSL) mouse model (Jinzenji et al, 2014). Intraperitoneal administration of tiagabine reversed SCI-induced neuropathic pain (Meisner, Marsh & Marsh, 2010).…”