Preclinical studies of the potent and selective nicotinic α4β2 receptor ligand VMY-2-95.
Preclinical studies of the potent and selective nicotinic α4β2 receptor ligand VMY-2-95.
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DOI：
10.1021/mp5003569
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发表时间：
2015-02-02
影响因子：
4.9
通讯作者：
Brown ML
中科院分区：
文献类型：
--
作者：
Kong H;Song JK;Yenugonda VM;Zhang L;Shuo T;Cheema AK;Kong Y;Du GH;Brown ML
拮抗神经元烟碱乙酰胆碱受体的小分子的发现和发展可能为抑郁症或成瘾模型的评估提供新的配体。我们发现了一种小分子VMY-2-95，这是一种对α4β2受体具有皮摩尔亲和力和高选择性的nAChR配体。在这项研究中，我们研究了它的临床前概况方面的溶解性，亲脂性，代谢稳定性，肠道渗透性，生物利用度和药物输送到大鼠大脑。在人肝微粒体上监测了VMY-2-95·2 HCl的代谢稳定性，并以高通量方式检测了VMY-2-95·2 HCl对CYP 1A 2、2C 9、2C 19、2D 6和3A 4底物代谢的比活性。用Caco-2细胞单层通透性法研究了VMY-2-95·2 HCl的肠转运。VMY-2-95·2 HCl易溶于水，化学性质稳定，表观分配系数为0.682。VMY-2-95·2 HCl对CYP 2C 9和2C 19有显著的抑制作用，但对1A 2、2D 6和3A 4的作用很弱或没有作用。Caco-2细胞模型研究表明，VMY-2-95·2 HCl具有高渗透性，外排率为1.11。VMY-2-95·2 HCl在0.9 h达到最大血清浓度0.56 mg/mL，口服半衰期为1.99 h。此外，经口给药3 mg/kg后，在大鼠脑中检测到VMY-2-95·2 HCl，并在60 min内达到最大脑组织浓度2.3 μg/g。总体而言，结果表明VMY-2-95·2 HCl具有良好的药物样性质，经口给药可穿透血脑屏障。
The discovery and development of small molecules that antagonize neuronal nicotinic acetylcholine receptors may provide new ligands for evaluation in models of depression or addiction. We discovered a small molecule, VMY-2-95, a nAChR ligand with picomolar affinity and high selectivity for α4β2 receptors. In this study, we investigated its preclinical profile in regards to solubility, lipophilicity, metabolic stability, intestinal permeability, bioavailability, and drug delivery to the rat brain. Metabolic stability of VMY-2-95·2HCl was monitored on human liver microsomes, and specific activity of VMY-2-95·2HCl on substrate metabolism by CYP1A2, 2C9, 2C19, 2D6, and 3A4 was tested in a high-throughput manner. The intestinal transport of VMY-2-95·2HCl was studied through Caco-2 cell monolayer permeability. VMY-2-95·2HCl was soluble in water and chemically stable, and the apparent partition coefficient was 0.682. VMY-2-95·2HCl showed significant inhibition of CYP2C9 and 2C19, but weak or no effect on 1A2, 2D6, and 3A4. The Caco-2 cell model studies revealed that VMY-2-95·2HCl was highly permeable with efflux ratio of 1.11. VMY-2-95·2HCl achieved a maximum serum concentration of 0.56 mg/mL at 0.9 h and was orally available with a half-life of ∼9 h. Furthermore, VMY-2-95·2HCl was detected in the rat brain after 3 mg/kg oral administration and achieved a maximal brain tissue concentration of 2.3 μg/g within 60 min. Overall, the results demonstrate that VMY-2-95·2HCl has good drug like properties and can penetrate the blood–brain barrier with oral administration.
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DOI：
10.1602/neurorx.2.4.554
发表时间：
2005-10-01
期刊：
NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
Alavijeh, Mohammad S;Chishty, Mansoor;Palmer, Alan M
通讯作者：
Palmer, Alan M
影响因子：
7.3
作者：
Bey, Emmanuel;Marchais-Oberwinkler, Sandrine;Hartmann, Rolf W.
通讯作者：
Hartmann, Rolf W.
影响因子：
2
作者：
Konsoula, Zacharoula;Jung, Mira
通讯作者：
Jung, Mira
影响因子：
2.7
作者：
Madgula, Vamsi L. M.;Avula, Bharathi;Khan, Shabana I.
通讯作者：
Khan, Shabana I.
DOI：
10.1016/0006-291x(91)91647-u
发表时间：
1991-03-29
影响因子：
3.1
作者：
ARTURSSON, P;KARLSSON, J
通讯作者：
KARLSSON, J