LY404187
(Synonyms: N-[2-(4'-氰基联苯-4-基)丙基]-2-丙烷磺酰胺) 目录号 : GC45776
A positive allosteric modulator of AMPA receptors
Cas No.:211311-95-4
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LY404187 is a benzothiadiazide positive allosteric modulator of AMPA receptors.1 It increases glutamate-induced activation of GluR1i, -2i, -2o, -3i, and -4i subunit-containing AMPA receptors with EC50 values of 5.65, 0.15, 1.44, 1.66, and 0.21 μM, respectively, in a calcium influx assay. LY404187 is selective for these AMPA receptors over GluR6 subunit-containing kainate receptors at 10 μM. LY404187 increases currents induced by glutamate and AMPA in rat prefrontal cortex pyramidal neurons (EC50s = 1.3 and 1.2 μM, respectively) but not in AMPA-stimulated primary rat embryonic hippocampal or primary cerebellar Purkinje neurons.2,3 LY404187 prevents decreases in the number of dopaminergic neurons in the substantia nigra induced by MPTP and 6-OHDA in mouse and rat, respectively, models of Parkinson's disease when administered at a dose of 0.5 mg/kg per day.4
|1. Miu, P., Jarvie, K.R., Radhakrishnan, V., et al. Novel AMPA receptor potentiators LY392098 and LY404187: Effects on recombinant human AMPA receptors in vitro. Neuropharmacology 40(8), 976-983 (2001).|2. Baumbarger, P.J., Muhlhauser, M., Zhai, J., et al. Positive modulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in prefrontal cortical pyramidal neurons by a novel allosteric potentiator. J. Pharmacol. Exp. Ther. 298(1), 86-102 (2001).|3. Gates, M., Ogden, A., and Bleakman, D. Pharmacological effects of AMPA receptor potentiators LY392098 and LY404187 on rat neuronal AMPA receptors in vitro. Neuropharmacology 40(8), 984-991 (2001).|4. O'Neill, M.J., Murray, T.K., Whalley, K., et al. Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson's disease. Eur. J. Pharmacol. 486(2), 163-174 (2004).
| Cas No. | 211311-95-4 | SDF | |
| 别名 | N-[2-(4'-氰基联苯-4-基)丙基]-2-丙烷磺酰胺 | ||
| Canonical SMILES | CC(CNS(C(C)C)(=O)=O)C(C=C1)=CC=C1C2=CC=C(C#N)C=C2 | ||
| 分子式 | C19H22N2O2S | 分子量 | 342.5 |
| 溶解度 | DMF: 15mg/mL,DMSO: 15mg/mL,DMSO:PBS (pH 7.2) (1:4): 0.2mg/mL,Ethanol: 3mg/mL | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.9197 mL | 14.5985 mL | 29.1971 mL |
| 5 mM | 0.5839 mL | 2.9197 mL | 5.8394 mL |
| 10 mM | 0.292 mL | 1.4599 mL | 2.9197 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
LY404187: a novel positive allosteric modulator of AMPA receptors
CNS Drug Rev 2002 Fall;8(3):255-82.PMID:12353058DOI:10.1111/j.1527-3458.2002.tb00228.x.
LY404187 is a selective, potent and centrally active positive allosteric modulator of AMPA receptors. LY404187 preferentially acts at recombinant human homomeric GluR2 and GluR4 versus GluR1 and GluR3 AMPA receptors. In addition, LY404187 potentiates the flip splice variant of these AMPA receptors to a greater degree than the flop splice variant. In both recombinant and native AMPA receptors, potentiation by LY404187 displays a unique time-dependent growth that appears to involve a suppression of the desensitization process of these ion channels. LY404187 has been shown to enhance glutamatergic synaptic transmission both in vitro and in vivo. This augmentation of synaptic activity is due to the direct potentiation of AMPA receptor function, as well as an indirect recruitment of voltage-dependent NMDA receptor activity. Enhanced calcium influx through NMDA receptors is known to be a critical step in initiating long-term modifications in synaptic function (e.g., long-term potentiation, LTP). These modifications in synaptic function may be substrates for certain forms of memory encoding. Consistent with a recruitment of NMDA receptor activity, LY404187 has been shown to enhance performance in animal models of cognitive function requiring different mnemonic processes. These data suggest that AMPA receptor potentiators may be therapeutically beneficial for treating cognitive deficits in a variety of disorders, particularly those that are associated with reduced glutamatergic signaling such as schizophrenia. In addition, LY404187 has been demonstrated to be efficacious in animal models of behavioral despair that possess considerable predictive validity for antidepressant activity. Although the therapeutic efficacy of AMPA receptor potentiators in these and other diseases will ultimately be determined in the clinic, evidence suggests that the benefit of these compounds will be mediated by multiple mechanisms of action. These mechanisms include direct enhancement of AMPA receptor function, secondary mobilization of intracellular signaling cascades, and prolonged modulation of gene expression.
LY404187, a potentiator of AMPARs, enhances both the amplitude and 1/CV2 of AMPA EPSCs but not NMDA EPSCs at CA3-CA1 synapses in the hippocampus of neonatal rats
Neurosci Lett 2012 Dec 7;531(2):193-7.PMID:23103715DOI:10.1016/j.neulet.2012.10.020.
Cyclothiazide is a well-known AMPAR potentiator, but it has also been shown to enhance the probability of presynaptic release in some cases. Interestingly, cyclothiazide has been shown to reveal AMPA EPSCs at silent CA3-CA1 synapses (which exhibit NMDA EPSCs but not AMPA EPSCs) in the hippocampus of neonatal or developing rats, but this particular result has not been reproduced at other types of synapses. Although this discrepancy may be due to the different mechanisms underlying silent synapses in distinct brain subregions, it is also possible that cyclothiazide has pre- and postsynaptic molecular targets that are differentially expressed at the different types (or different developing stages) of synapses. In this study, we reexamined, using a new AMPAR potentiator, LY404187, whether AMPAR potentiation leads to the conversion of silent CA3-CA1 synapses into functional synapses (exhibiting both AMPA and NMDA EPSCs) in the hippocampus of neonatal rats. LY404187 did not appear to alter the probability of presynaptic release, as evidenced by the lack of significant changes in both the amplitude and the paired-pulse facilitation ratio (an index of release probability) of NMDA EPSCs. LY404187 enhanced both the amplitude and 1/CV(2) (CV: coefficient of variation) of AMPA EPSCs but not NMDA EPSCs. Because an increase in 1/CV(2) reflects an increased number of functional synapses and/or an enhanced release probability, the LY404187-induced increase in the 1/CV(2) value of AMPA EPSCs, but not NMDA EPSCs, likely indicates an increased number of synapses exhibiting AMPA EPSCs but not an increased number of synapses exhibiting NMDA EPSCs. Because AMPARs and NMDARs are co-localized at the same synapses, our findings are consistent with a scenario in which LY404187 enables silent synapses to acquire AMPA EPSCs.
The AMPA receptor potentiator LY404187 increases cerebral glucose utilization and c-fos expression in the rat
J Cereb Blood Flow Metab 2004 Oct;24(10):1098-109.PMID:15529010DOI:10.1097/01.WCB.0000138665.25305.7C.
AMPA receptor potentiators enhance AMPA receptor-mediated glutamatergic neurotransmission and may have therapeutic potential as cognitive enhancers or antidepressants. The anatomical basis for the action of AMPA receptor potentiators is unknown. The aim of this study was to determine the effects of the biarylpropylsulfonamide AMPA receptor potentiator, LY404187 (0.05 to 5 mg/kg subcutaneously), upon cerebral glucose utilization and c-fos expression using 14C-2-deoxglucose autoradiography and c-fos immunocytochemistry. LY404187 (0.5 mg/kg) produced significant elevations in glucose utilization in 28 of the 52 anatomical regions analyzed, which included rostral neocortical areas and the hippocampus, as well the dorsal raphe nucleus, lateral habenula, and locus coeruleus. No significant decreases in glucose utilization were observed in any region after LY404187 administration. The increases in glucose utilization with LY404187 (0.5 mg/kg) were blocked by pretreatment with the AMPA receptor antagonist LY293558 (25 mg/kg), indicating that LY404187 acts through AMPA receptor-mediated mechanisms. LY404187 (0.5 mg/kg) also produced increases in c-fos immunoreactivity in the cortex, locus coeruleus, and the dorsal raphe nucleus. These studies demonstrate neuronal activation in key brain areas that are associated with memory processes and thus provide an anatomical basis for the cognitive enhancing effects of AMPA receptor potentiators.
Novel AMPA receptor potentiators LY392098 and LY404187: effects on recombinant human AMPA receptors in vitro
Neuropharmacology 2001 Jun;40(8):976-83.PMID:11406188DOI:10.1016/s0028-3908(01)00027-2.
The present study describes the activity of two novel potent and selective AMPA receptor potentiator molecules LY392098 and LY404187. LY392098 and LY404187 enhance glutamate (100 microM) stimulated ion influx through recombinant homomeric human AMPA receptor ion channels, GluR1-4, with estimated EC(50) values of 1.77 microM (GluR1(i)), 0.22 microM (GluR2(i)), 0.56 microM (GluR2(o)), 1.89 microM (GluR3(i)) and 0.20 microM (GluR4(i)) for LY392098 and EC(50) values of 5.65 microM (GluR1(i)), 0.15 microM (GluR2(i)), 1.44 microM (GluR2(o)), 1.66 microM (GluR3(i)) and 0.21 microM (GluR4(i)) for LY404187. Neither compound affected ion influx in untransfected HEK293 cells or GluR transfected cells in the absence of glutamate. Both compounds were selective for activity at AMPA receptors, with no activity at human recombinant kainate receptors. Electrophysiological recordings demonstrated that glutamate (1 mM)-evoked inward currents in human GluR4 transfected HEK293 cells were potentiated by LY392098 and LY404187 at low concentrations (3-10 nM). In addition, both compounds removed glutamate-dependent desensitization of recombinant GluR4 AMPA receptors. These studies demonstrate that LY392098 and LY404187 allosterically potentiate responses mediated by human AMPA receptor ion channels expressed in HEK 293 cells in vitro.
Pharmacological effects of AMPA receptor potentiators LY392098 and LY404187 on rat neuronal AMPA receptors in vitro
Neuropharmacology 2001 Jun;40(8):984-91.PMID:11406189DOI:10.1016/s0028-3908(01)00040-5.
The present study describes the pharmacological activity of two novel positive allosteric modulators at AMPA receptors in acutely isolated rat cerebellar Purkinje neurons and cultured rat hippocampal neurons. Currents elicited by application of glutamate (100 microM) to isolated cerebellar Purkinje neurons were potentiated by LY392098, LY404187, cyclothiazide, CX516 and aniracetam. The rank order of potency was LY404187> LY392098> cyclothiazide > CX516> aniracetam. LY392098 displayed a higher maximal efficacy than the other compounds examined. AMPA-activated inward currents in cultured rat hippocampal neurons were potentiated by LY392098, LY404187 and cyclothiazide in a reversible and concentration-dependent manner although considerable heterogeneity in the magnitude of response from cell to cell was observed. LY392098 was ineffective in potentiating AMPA receptor responses when dialyzed via the intracellular solution. The selectivity profiles of the two novel AMPA receptor potentiators were examined. LY392098 or LY404187 had minimal activity on NMDA receptor responses, on voltage-gated calcium channel currents in cultured hippocampal neurons and on GluR5 kainate receptor currents in acutely isolated rat dorsal root ganglion neurons.