Encenicline

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

Encenicline 是一种选择性 α7 烟碱乙酰胆碱受体 (nAChRs) 激动剂，正在开发用于治疗精神分裂症和阿尔茨海默病的认知障碍。

Encenicline is a selective α7 nicotinic acetylcholine receptor?(nAChRs) agonist in development for treating cognitive impairment in schizophrenia and Alzheimer's disease.

Encenicline (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). Encenicline (EVP-6124) is approximately 300 fold more potent than the natural agonist ACh (Ki=3 μM), measured in binding assays using [3H]-MLA. Encenicline 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, Encenicline shows selectivity for α7 nAChRs and does not activate or inhibit heteromeric α4β2 nAChRs.

Encenicline (EVP-6124) has good brain penetration and an adequate exposure time. Encenicline (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 Encenicline 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, Encenicline 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.). Encenicline (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., Encenicline (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. Pharmacokinetic studies have shown that Encenicline (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. Encenicline (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 .

EVP-6124

Endocrinology/Hormones

AChR

nAChR

——

——

550999-75-2

320.84

C16H17ClN2OS

>98% (HPLC)

——

Clc1cccc2cc(sc12)C(=O)N[C@H]1CN2CCC1CC2

N-[(3R)-1-Azabicyclo[2.2.2]octan-3-yl]-7-chloro-1-benzothiophene-2-carboxamide

(-20℃)

With Ice Pack

≥ 2 years