EVP-6124NAChRs agonist CAS# 550999-75-2 |
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| Cas No. | 550999-75-2 | SDF | Download SDF |
| PubChem ID | 46196517 | Appearance | Powder |
| Formula | C16H17ClN2OS | M.Wt | 320.84 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | Encenicline | ||
| Solubility | DMSO | ||
| Chemical Name | N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-7-chloro-1-benzothiophene-2-carboxamide | ||
| SMILES | C1CN2CCC1C(C2)NC(=O)C3=CC4=C(S3)C(=CC=C4)Cl | ||
| Standard InChIKey | SSRDSYXGYPJKRR-ZDUSSCGKSA-N | ||
| Standard InChI | InChI=1S/C16H17ClN2OS/c17-12-3-1-2-11-8-14(21-15(11)12)16(20)18-13-9-19-6-4-10(13)5-7-19/h1-3,8,10,13H,4-7,9H2,(H,18,20)/t13-/m0/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | EVP-6124 is a novel partial agonist of α7 neuronal nicotinic acetylcholine receptors (nAChRs).In Vitro:EVP-6124 displaces [3H]-MLA (Methyllycaconitine) (Ki=9.98 nM, pIC50=7.65±0.06, n=3) and [125I]-α-bungarotoxin (Ki=4.33 nM, pIC50=8.07±0.04, n=3). EVP-6124 is approximately 300 fold more potent than the natural agonist ACh (Ki=3 μM), measured in binding assays using [3H]-MLA. EVP-6124 inhibits the 5-HT3 receptor by 51% at 10 nM, the lowest concentration tested. Evaluation of the human 5-HT2B receptor expressed in CHO cells demonstrates displacement of [3H]-mesulergine (Ki=14 nM) and only antagonist activity in the rat gastric fundus assay at an IC50 of 16 μM. In binding and functional experiments, EVP-6124 shows selectivity for α7 nAChRs and does not activate or inhibit heteromeric α4β2 nAChRs[1].In Vivo:EVP-6124 has good brain penetration and an adequate exposure time. EVP-6124 (0.3 mg/kg, p.o.) significantly restores memory function in scopolamine-treated rats (0.1 mg/kg, i.p.) in an object recognition task (ORT). Although donepezil at 0.1 mg/kg, p.o. or EVP-6124 at 0.03 mg/kg, p.o. did not improve memory in this task, co-administration of these sub-efficacious doses fully restored memory. In a natural forgetting test, an ORT with a 24 h retention time, EVP-6124 improved memory at 0.3 mg/kg, p.o. This improvement is blocked by the selective α7 nAChR antagonist methyllycaconitine (0.3 mg/kg, i.p. or 10 μg, i.c.v.). EVP-6124 is found to bind moderately to rat plasma proteins with a mean fu of 0.11±0.01 (mean±SD) or 11%. Over a range of 0.1-30 mg/kg, p.o., EVP-6124 demonstrates proportional dose escalation. Tmax is at 4 h in plasma and 2 h brain, although the brain concentrations remained similar between 2 and 8 h. The B:P ratios are 1.7-5.1 between 1 and 8 h[1].Pharmacokinetic studies have shown that EVP-6124 (0.4 mg/kg, i.p.) reaches peak brain concentration 2 hr after administration and remains at effective concentrations for at least 4 hr. EVP-6124 is administered to WT mice at ZT0 (0.4 mg/kg i.p single dose) and significantly increases the saturation index of NMDARs in slices obtained 4 hr later without causing prolonged wakefulness or enhanced locomotor activity [2]. References: | |||||
EVP-6124 Dilution Calculator
EVP-6124 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 3.1168 mL | 15.5841 mL | 31.1682 mL | 62.3364 mL | 77.9205 mL |
| 5 mM | 0.6234 mL | 3.1168 mL | 6.2336 mL | 12.4673 mL | 15.5841 mL |
| 10 mM | 0.3117 mL | 1.5584 mL | 3.1168 mL | 6.2336 mL | 7.792 mL |
| 50 mM | 0.0623 mL | 0.3117 mL | 0.6234 mL | 1.2467 mL | 1.5584 mL |
| 100 mM | 0.0312 mL | 0.1558 mL | 0.3117 mL | 0.6234 mL | 0.7792 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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EVP-6124 is a partial agonist of α7 neuronal nicotinic acetylcholine receptors (nAChRs) that was proved high-affinity in vitro and in vivo. [1]
EVP-6124 was proved to show selectivity for α7 but low-affinity of α4β2 nAChRs in some binding and functional experiments. EVP-6124 had good brain penetration and an adequate exposure time. [1,2]
Co-administration of EVP-6124 and the selective nAChRs antagonist could contribute to the release of DA, ACH, and Glu. This could be used to treat cognitive impairment and possibly other dimensions of psychopathology. Co-administration of donepezil at 0.1 mg/kg, p.o. and EVP-6124 at 0.03 mg/kg proved to be fully restored memory while each of these did not improve memory in this task. [1] Pretreatment with the selective α7 nAChR antagonist, methyllycaconitine (MLA, 1.0 mg/kg), significantly blocked cortical DA and Glu efflux induced by EVP-6124 (0.1 mg/kg). [2,3]
References:
1. Jos Prickaerts, Nick P. van Goethem, et al. EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors. Neuropharmacology, 2012,62 (2): 1099-1110.
2. Mei Huang, Anna R. Felix, et al. Chaya Bhuvaneswaran, Dana Hilt, Gerhard K?nig, Herbert Y. Meltzer, The alpha-7 receptor agonist EVP-6124 increases dopamine and glutamate efflux in rat medial prefrontal cortex and nucleus accumbens. Biochemical Pharmacology, 2011, 82 (8): 1040.
3. Mei Huang, Anna R. Felix, et al. The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens. Psychopharmacology, 2014, 231:4541-4551.
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Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication.[Pubmed:25495510]
Expert Rev Neurother. 2015 Jan;15(1):7-17.
Alzheimer's disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an alpha7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the alpha7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III trials under the title COGNITIV AD will assess the efficacy and tolerability of EVP-6124 in patients with mild-to-moderate AD. Based on the completed clinical trials and proposed mechanism of action, EVP-6124 would appear to be a good candidate for therapy in combination with cholinesterase inhibitors.
Continuous infusion of the alpha7 nicotinic acetylcholine receptor agonist EVP-6124 produces no signs of tolerance at memory-enhancing doses in rats: a pharmacokinetic and behavioral study.[Pubmed:25794332]
Behav Pharmacol. 2015 Jun;26(4):403-6.
We investigated whether the effects of acutely administered EVP-6124, an alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonist, on cognition were maintained after 6-day continuous minipump administration. Performance in a delay-dependent forgetting test was measured in the object recognition task after single-oral doses of 0.3 or 1 mg/kg, or at plasma steady-state concentrations (Css) of 0.6 or 2 ng/ml, which were similar to the efficacious plasma concentrations after single-oral dosing. The 0.3 mg/kg acute dose enhanced memory at a total plasma concentration of approximately 0.3 ng/ml at 1-4 h after dosing. Continuous treatment produced total plasma Css values of 0.48 and 1.93 ng/ml on day 6 and enhanced memory. At EVP-6124 plasma concentrations that optimally enhance memory in the object recognition task, tolerance did not develop after 6 days of continuous treatment.
The role of proof of concept (POC) studies in drug development using the EVP-6124 POC study as an example.[Pubmed:24419310]
J Psychiatr Pract. 2014 Jan;20(1):59-60.
The goal of early proof of concept studies, typically involving a small number of subjects and more latitude in statistical requirements, is to provide evidence that a drug is likely to be successful in later stages of drug development. Although often not published, such studies allow drug developers to make "Go/No Go" decisions about proceeding with larger, more expensive studies.
The novel alpha7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens.[Pubmed:24810107]
Psychopharmacology (Berl). 2014 Dec;231(23):4541-51.
BACKGROUND: Alpha7 and alpha4beta2 nicotinic acetylcholine receptor (nAChR) agonists have been shown to improve cognition in various animal models of cognitive impairment and are of interest as treatments for schizophrenia, Alzheimer's disease, and other cognitive disorders. Increased release of dopamine (DA), acetylcholine (ACh), glutamate (Glu), and gamma-aminobutyric acid (GABA) in cerebral cortex, hippocampus, and nucleus accumbens (NAC) has been suggested to contribute to their beneficial effects on cognition. RESULTS: Using in vivo microdialysis, we found that EVP-6124 [(R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide], a high-affinity alpha7 nAChR partial agonist, at 0.1 mg/kg, s.c., increased DA efflux in the medial prefrontal cortex (mPFC) and NAC. EVP-6124, 0.1 and 0.3 mg/kg, also increased efflux of ACh in the mPFC but not in the NAC. Similarly, EVP-6124, 0.1 mg/kg, but not 0.03 and 0.3 mg/kg, significantly increased mPFC Glu efflux. Thus, EVP-6124 produced an inverted U-shaped curve for DA and Glu release, as previously reported for other alpha7 nAChR agonists. The three doses of EVP-6124 did not produce a significant effect on GABA efflux in either region. Pretreatment with the selective alpha7 nAChR antagonist, methyllycaconitine (MLA, 1.0 mg/kg), significantly blocked cortical DA and Glu efflux induced by EVP-6124 (0.1 mg/kg), suggesting that the effects of EVP-6124 on these neurotransmitters were due to alpha7 nAChR agonism. MLA only partially blocked the effects of EVP-6124 on ACh efflux in the mPFC. CONCLUSION: These results suggest increased cortical DA, ACh, and Glu release, which may contribute to the ability of the alpha7 nAChR agonist, EVP-6124, to treat cognitive impairment and possibly other dimensions of psychopathology.
