EVP-6124 hydrochloride

EVP-6124 Hydrochloride is a hydrochloride form of EVP-6124. EVP-6124 is 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.

Development of Automated Patch Clamp Assay for Evaluation of alpha7 Nicotinic Acetylcholine Receptor Agonists in Automated QPatch-16.[Pubmed:25880723]

Assay Drug Dev Technol. 2015 Apr;13(3):174-84.

The alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) is an important and challenging target for drug discovery in the area of neuropsychiatric disorders. The current screening for chemicals targeting alpha7 nAChRs is primarily achieved by the use of low-throughput assay two-electrode voltage clamp (TEVC) in nonmammalian Xenopus oocytes. Automated patch clamp system has emerged as an attractive approach compared to conventional electrophysiology. To develop a mammalian cell-based functional assay in an automated electrophysiology system, we in this study generated a stable expression of alpha7 nAChRs in GH3 cells that originated from a rat pituitary tumor cell line and utilized automated QPatch-16 to test a set of tool compounds and chemicals identified as alpha7 agonists by TEVC. For the improvement of evaluating weak or partial alpha7 nAChRs agonists, we achieved enhancement of the signal-to-noise ratio by the addition of a positive allosteric modulator PNU-120596, which only activates alpha7 current in the presence of agonist. This improved assay was further validated by using known alpha7 partial agonists, such as RG3487, EVP-6124, and A-P90. Using this validated assay, we were able to identify a novel agonist 140507C that partially activates alpha7 nAChRs. Taken together, our results validate the use of QPatch-16 for evaluation alpha7 partial agonists, demonstrating its utility as an effective tool for alpha7 ion channel drug discovery.

Encenicline hydrochloride (EVP-6124 hydrochloride) is a novel partial agonist of α7 neuronal nicotinic acetylcholine receptors (nAChRs).

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