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SR 95531 hydrobromide Sale

(Synonyms: 克他命,Gabazine) 目录号 : GC10101

A GABAA receptor antagonist

SR 95531 hydrobromide Chemical Structure

Cas No.:104104-50-9

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥495.00
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5mg
¥450.00
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10mg
¥800.00
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25mg
¥1,500.00
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50mg
¥2,475.00
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100mg
¥4,425.00
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Sample solution is provided at 25 µL, 10mM.

产品文档

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实验参考方法

Animal experiment [1]:

Animal models

Male ICR mice

Preparation Method

Effects of 5-aminovaleric acid (5-AVA) and SR 95531 injected intrathecally (i.t.) on inhibition of the tail-flick response induced by DSC administered i.t. Saline (5 µl), 5-AVA (from 1 to 20 µg) or SR 95531 (from 0.1 to 2 ng) was pretreated i.t. 10 min before i.t. administration of DSC (30 µg) or vehicle.

Dosage form

injected intrathecally, 0.1 to 2 ng

Applications

SR 95531 attenuated i.t. administered DSC-induced inhibition of the tail-flick response in a dose-dependent manner.

References:

[1]: Suh H W, Song D K, Huh S O, et al. Antinociceptive mechanisms of Dipsacus saponin C administered intrathecally in mice[J]. Journal of ethnopharmacology, 2000, 71(1-2): 211-218.

产品描述

SR 95531 hydrobromide (Gabazine) to be a selective antagonist at the GABA binding sites on GABAA receptors [1]. SR 95531 hydrobromide partially inhibited direct activation of the receptor by the barbiturate pentobarbital and by the steroid alphaxolone, possibly by acting as an allosteric inhibitor of GABAA receptor channel opening [2].

SR 95531 hydrobromide had antagonist potency response against to the binding of GABA and recombination α1β2γ2S GABAA receptors, with the IC50 of 349 nM [1]. The competitive antagonist SR 95531 hydrobromide showed similar potency on both cell types with IC50's of 196 nM and 224 nM on α4β3γ2 receptors and α4β3δ receptors respectively [3]. In αTC1-9 cells, GABA (10 μmol/l) significantly suppressed glucagon secretion to ~50% of control levels, whereas in the presence of SR 95531 hydrobromide (10 μmol/l), exogenous GABA exerted no significant effect on glucagon secretion [4].

SR 95531 hydrobromide administered i.t. effectively attenuated antinociception induced by i.t. administered Dipsacus saponin C (DSC) [5].

References:
[1]. Iqbal F, Ellwood R, Mortensen M, et al. Synthesis and evaluation of highly potent GABAA receptor antagonists based on gabazine (SR-95531)[J]. Bioorganic & medicinal chemistry letters, 2011, 21(14): 4252-4254.
[2]. Ueno S, Bracamontes J, Zorumski C, et al. Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor[J]. Journal of Neuroscience, 1997, 17(2): 625-634.
[3]. Brown N, Kerby J, Bonnert T P, et al. Pharmacological characterization of a novel cell line expressing human α4β3δ GABAA receptors[J]. British journal of pharmacology, 2002, 136(7): 965-974.
[4]. Bailey S J, Ravier M A, Rutter G A. Glucose-dependent regulation of γ-aminobutyric acid (GABAA) receptor expression in mouse pancreatic islet α-cells[J]. Diabetes, 2007, 56(2): 320-327.
[5]. Suh H W, Song D K, Huh S O, et al. Antinociceptive mechanisms of Dipsacus saponin C administered intrathecally in mice[J]. Journal of ethnopharmacology, 2000, 71(1-2): 211-218.

SR 95531 氢溴酸盐 (Gabazine) 是 GABAA 受体上 GABA 结合位点的选择性拮抗剂 [1]。 SR 95531 氢溴酸盐部分抑制巴比妥类戊巴比妥和类固醇阿尔法索酮对受体的直接激活,可能是作为 GABAA 受体通道开放的变构抑制剂[2]

SR 95531 hydrobromide 对 GABA 和重组 α1β2γ2S GABAA 受体的结合具有拮抗作用,IC50 为 349 nM [1]。竞争性拮抗剂 SR 95531 hydrobromide 对两种细胞类型显示相似的效力,对 α4β3γ2 受体和 α4β3δ 受体的 IC50 分别为 196 nM 和 224 nM [3]。在 αTC1-9 细胞中,GABA (10 μmol/l) 将胰高血糖素分泌显着抑制至对照水平的 50%,而在 SR 95531 氢溴酸盐 (10 μmol/l) 存在的情况下,外源性 GABA 对胰高血糖素分泌没有显着影响 < sup>[4].

SR 95531 氢溴酸盐给药于它。有效减弱 it 诱导的抗伤害作用给予续断皂甙 C (DSC) [5]

Chemical Properties

Cas No. 104104-50-9 SDF
别名 克他命,Gabazine
化学名 4-(6-imino-3-(4-methoxyphenyl)pyridazin-1(6H)-yl)butanoic acid hydrobromide
Canonical SMILES COC1=CC=C(C(C=CC2=N)=NN2CCCC(O)=O)C=C1.Br
分子式 C15H17N3O3.HBr 分子量 368.23
溶解度 MeOH:PBS (pH 7.2); (1:1): 0.5 mg/ml,Methanol: 1 mg/ml 储存条件 Store at 4°C
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1 mM 2.7157 mL 13.5785 mL 27.1569 mL
5 mM 0.5431 mL 2.7157 mL 5.4314 mL
10 mM 0.2716 mL 1.3578 mL 2.7157 mL
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Research Update

Agonist-, antagonist-, and benzodiazepine-induced structural changes in the alpha1 Met113-Leu132 region of the GABAA receptor

The structural basis by which agonists, antagonists, and allosteric modulators exert their distinct actions on ligand-gated ion channels is poorly understood. We used the substituted cysteine accessibility method to probe the structure of the GABAA receptor in the presence of ligands that elicit different pharmacological effects. Residues in the alpha1 Met113-Leu132 region of the GABA binding site were individually mutated to cysteine and expressed with wild-type beta2 and gamma2 subunits in Xenopus laevis oocytes. Using electrophysiology, we determined the rates of reaction of N-biotinaminoethyl methaneth-iosulfonate (MTSEA-biotin) with the introduced cysteines in the resting (unliganded) state and compared them with rates determined in the presence of GABA (agonist), 4-[6-imino-3-(4-methoxyphenyl)pyridazin-1-yl]butanoic acid hydrobromide (SR-95531; antagonist), pentobarbital (allosteric modulator), and flurazepam (allosteric modulator). alpha1N115C, alpha1L117C, alpha1T129C, and alpha1R131C are predicted to line the GABA binding pocket because MTSEA-biotin modification of these residues decreased the amount of current elicited by GABA, and the rates/extents of modification were decreased both by GABA and SR-95531. Reaction rates of some substituted cysteines were different depending on the ligand, indicating that barbiturate- and GABA-induced channel gating, antagonist binding, and benzodiazepine modulation induce specific structural rearrangements. Chemical reactivity of alpha1E122C was decreased by either GABA or pentobarbital but was unaltered by SR-95531 binding, whereas alpha1L127C reactivity was decreased by agonist and antagonist binding but not affected by pentobarbital. Furthermore, alpha1E122C, alpha1L127C, and alpha1R131C changed accessibility in response to flurazepam, providing structural evidence that residues in and near the GABA binding site move in response to benzodiazepine modulation.

The GABAA antagonist DPP-4-PIOL selectively antagonises tonic over phasic GABAergic currents in dentate gyrus granule cells

GABAA receptors mediate two different types of inhibitory currents: phasic inhibitory currents when rapid and brief presynaptic GABA release activates postsynaptic GABAA receptors and tonic inhibitory currents generated by low extrasynaptic GABA levels, persistently activating extrasynaptic GABAA receptors. The two inhibitory current types are mediated by different subpopulations of GABAA receptors with diverse pharmacological profiles. Selective antagonism of tonic currents is of special interest as excessive tonic inhibition post-stroke has severe pathological consequences. Here we demonstrate that phasic and tonic GABAA receptor currents can be selectively inhibited by the antagonists SR 95531 and the 4-PIOL derivative, 4-(3,3-diphenylpropyl)-5-(4-piperidyl)-3-isoxazolol hydrobromide (DPP-4-PIOL), respectively. In dentate gyrus granule cells, SR 95531 was found approximately 4 times as potent inhibiting phasic currents compared to tonic currents (IC50 values: 101 vs. 427 nM). Conversely, DPP-4-PIOL was estimated to be more than 20 times as potent inhibiting tonic current compared to phasic current (IC50 values: 0.87 vs. 21.3 nM). Consequently, we were able to impose a pronounced reduction in tonic GABA mediated current (>70 %) by concentrations of DPP-4-PIOL, at which no significant effect on the phasic current was seen. Our findings demonstrate that selective inhibition of GABA mediated tonic current is possible, when targeting a subpopulation of GABAA receptors located extrasynaptically using the antagonist, DPP-4-PIOL.

Diminished cortical inhibition in an aging mouse model of chronic tinnitus

Flavoprotein autofluorescence imaging was used to examine auditory cortical synaptic responses in aged animals with behavioral evidence of tinnitus and hearing loss. Mice were exposed to noise trauma at 1-3 months of age and were assessed for behavioral evidence of tinnitus and hearing loss immediately after the noise trauma and again at ~24-30 months of age. Within 2 months of the final behavioral assessment, auditory cortical synaptic transmission was examined in brain slices using electrical stimulation of putative thalamocortical afferents, and flavoprotein autofluorescence imaging was used to measure cortical activation. Noise-exposed animals showed a 68% increase in amplitude of cortical activation compared with controls (p = 0.008), and these animals showed a diminished sensitivity to GABA(A)ergic blockade (p = 0.008, using bath-applied 200 nm SR 95531 [6-Imino-3-(4-methoxyphenyl)-1(6H)-p yridazinebutanoic acid hydrobromide]). The strength of cortical activation was significantly correlated to the degree of tinnitus behavior, assessed via a loss of gap detection in a startle paradigm. The decrease in GABA(A) sensitivity was greater in the regions of the cortex farther away from the stimulation site, potentially reflecting a greater sensitivity of corticocortical versus thalamocortical projections to the effects of noise trauma. Finally, there was no relationship between auditory cortical activation and activation of the somatosensory cortex in the same slices, suggesting that the increases in auditory cortical activation were not attributable to a generalized hyperexcitable state in noise-exposed animals. These data suggest that noise trauma can cause long-lasting changes in the auditory cortical physiology and may provide specific targets to ameliorate the effects of chronic tinnitus.

Effects of endocannabinoids on discharge of baroreceptive NTS neurons

Previously, we have shown that microinjection of endocannabinoids (ECBs) into the nucleus tractus solitarius (NTS) can modulate baroreflex control of blood pressure (BP), prolonging pressor-induced inhibition of renal sympathetic nerve activity. This suggests that ECBs can modulate excitability of baroreceptive neurons in the NTS. Studies by others have shown that neural cannabinoid (CB1) receptors are present on fibers in the NTS, suggesting that some presynaptic modulation of transmitter release could occur in this region which receives direct afferent projections from arterial baroreceptors and cardiac mechanoreceptors. This study, therefore, was performed to determine the effects of ECBs on NTS baroreceptive neuronal discharge. Picoinjection of the ECB anandamide (AEA) was found to significantly increase discharge of baroreceptive neurons (20 of 23). Picoinjection of the ECB uptake inhibitor, AM404, which enhances endogenous ECB activity, also significantly increased discharge of baroreceptive neurons (8 of 10 neurons). To determine if effects of ECBs involved a GABAA mechanism, the neuronal responses to AEA and AM404 were tested after prior blockade of postsynaptic GABAA receptors by bicuculline (BIC) or SR 95531 hydrobromide (gabazine--SR 95531), which would eliminate any effects due to modulation of GABA input. The increase in neuronal discharge to both AEA and AM404 was significantly attenuated following BIC or SR 95531, which alone significantly increased discharge of baroreceptive neurons tested. These results support the hypothesis that ECBs enhance baroreflex function through increases in NTS baroreceptive neuronal activity, due in part to modulation of GABAergic inhibitory effects at the neuronal level.