JNJ-46281222
目录号 : GC39393
JNJ-46281222 是选择性代谢型谷氨酸 2 (mGlu2) 高效 PAM (正构变构调节剂)，具有纳摩尔摩尔亲和力(Kd=1.7 nM) 和高调节效能 (pEC50 = 7.71) 的高效 PAM (正构变构调节剂)。
Cas No.:1254980-38-5
Sample solution is provided at 25 µL, 10mM.
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JNJ-46281222 is an metabotropic glutamate (mGlu) 2-selective, highly potent PAM (positive allosteric modulator) with nanomolar affinity (Kd = 1.7 nM) and a high modulatory potency (pEC50 = 7.71)[1].
[1]. Doornbos ML,et al. Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ-46281222.Br J Pharmacol. 2016 Feb;173(3):588-600.
| Cas No. | 1254980-38-5 | SDF | |
| Canonical SMILES | FC(C1=C(CN2CCC(C3=CC=CC=C3)CC2)C=CN4C1=NN=C4CC5CC5)(F)F | ||
| 分子式 | C23H25F3N4 | 分子量 | 414.47 |
| 溶解度 | DMSO: 62.5 mg/mL (150.79 mM) | 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。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4127 mL | 12.0636 mL | 24.1272 mL |
| 5 mM | 0.4825 mL | 2.4127 mL | 4.8254 mL |
| 10 mM | 0.2413 mL | 1.2064 mL | 2.4127 mL |
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| 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 |
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2.
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Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ-46281222
Br J Pharmacol 2016 Feb;173(3):588-600.PMID:26589404DOI:10.1111/bph.13390.
Background and purpose: Allosteric modulation of the mGlu2 receptor is a potential strategy for treatment of various neurological and psychiatric disorders. Here, we describe the in vitro characterization of the mGlu2 positive allosteric modulator (PAM) JNJ-46281222 and its radiolabelled counterpart [(3) H]-JNJ-46281222. Using this novel tool, we also describe the allosteric effect of orthosteric glutamate binding and the presence of a bound G protein on PAM binding and use computational approaches to further investigate the binding mode. Experimental approach: We have used radioligand binding studies, functional assays, site-directed mutagenesis, homology modelling and molecular dynamics to study the binding of JNJ-46281222. Key results: JNJ-46281222 is an mGlu2 -selective, highly potent PAM with nanomolar affinity (KD = 1.7 nM). Binding of [(3) H]-JNJ-46281222 was increased by the presence of glutamate and greatly reduced by the presence of GTP, indicating the preference for a G protein bound state of the receptor for PAM binding. Its allosteric binding site was visualized and analysed by a computational docking and molecular dynamics study. The simulations revealed amino acid movements in regions expected to be important for activation. The binding mode was supported by [(3) H]-JNJ-46281222 binding experiments on mutant receptors. Conclusion and implications: Our results obtained with JNJ-46281222 in unlabelled and tritiated form further contribute to our understanding of mGlu2 allosteric modulation. The computational simulations and mutagenesis provide a plausible binding mode with indications of how the ligand permits allosteric activation. This study is therefore of interest for mGlu2 and class C receptor drug discovery.
Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor
Pharmacol Res Perspect 2015 Feb;3(1):e00096.PMID:25692015DOI:10.1002/prp2.96.
Compounds modulating metabotropic glutamate type 2 (mGlu2) receptor activity may have therapeutic benefits in treating psychiatric disorders like schizophrenia and anxiety. The pharmacological and pharmacokinetic properties of a novel mGlu2 receptor-positive allosteric modulator (PAM), 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-2(1H)-pyridinone (JNJ-40411813/ADX71149) are described here. JNJ-40411813 acts as a PAM at the cloned mGlu2 receptor: EC50 = 147 ± 42 nmol/L in a [(35)S]GTPγS binding assay with human metabotropic glutamate type 2 (hmGlu2) CHO cells and EC50 = 64 ± 29 nmol/L in a Ca(2+) mobilization assay with hmGlu2 G α16 cotransfected HEK293 cells. [(35)S]GTPγS autoradiography on rat brain slices confirmed PAM activity of JNJ-40411813 on native mGlu2 receptor. JNJ-40411813 displaced [(3)H]JNJ-40068782 and [(3)H]JNJ-46281222 (mGlu2 receptor PAMs), while it failed to displace [(3)H]LY341495 (a competitive mGlu2/3 receptor antagonist). In rats, JNJ-40411813 showed ex vivo mGlu2 receptor occupancy using [(3)H]JNJ-46281222 with ED50 of 16 mg/kg (p.o.). PK-PD modeling using the same radioligand resulted in an EC50 of 1032 ng/mL. While JNJ-40411813 demonstrated moderate affinity for human 5HT2A receptor in vitro (K b = 1.1 μmol/L), higher than expected 5HT2A occupancy was observed in vivo (in rats, ED50 = 17 mg/kg p.o.) due to a metabolite. JNJ-40411813 dose dependently suppressed REM sleep (LAD, 3 mg/kg p.o.), and promoted and consolidated deep sleep. In fed rats, JNJ-40411813 (10 mg/kg p.o.) was rapidly absorbed (C max 938 ng/mL at 0.5 h) with an absolute oral bioavailability of 31%. Collectively, our data show that JNJ-40411813 is an interesting candidate to explore the therapeutic potential of mGlu2 PAMs, in in vivo rodents experiments as well as in clinical studies.