Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity

被引：20

作者：

Berry, Cynthia B. ^{[1
,2
,3
]}

Bubser, Michael ^{[2
,4
]}

Jones, Carrie K. ^{[2
,4
]}

Hayes, John P. ^{[1
,2
]}

Wepy, James A. ^{[1
,2
]}

Locuson, Charles W. ^{[2
,3
,4
]}

Daniels, J. Scott ^{[2
,3
,4
]}

Lindsey, Craig W. ^{[1
,2
,3
,4
]}

Hopkins, Corey R. ^{[1
,2
,3
,4
]}

机构：

[1] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[3] Vanderbilt Specialized Chem Ctr Probe Dev MLPCN, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 09期

关键词：

Dopamine 4 receptor antagonist; ML398; addiction; MLPCN; NOVELTY SEEKING; DOPAMINE-RECEPTORS; SUBSTANCE-ABUSE; COCAINE; MICE; SCHIZOPHRENIA; L-745,870; GENE; SAGA; POLYMORPHISM;

D O I：

10.1021/ml500267c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein, we report the structureactivity relationship of a chiral morpholine-based scaffold, which led to the identification of a potent and selective dopamine 4 (D-4) receptor antagonist. The 4-chlorobenzyl moiety was identified, and the compound was designated an MLPCN probe molecule, ML398. ML398 is potent against the D-4 receptor with IC50 = 130 nM and K-i = 36 nM and shows no activity against the other dopamine receptors tested (>20 mu M against D1, D2S, D2L, D3, and D5). Further in vivo studies showed that ML398 reversed cocaine-induced hyperlocomotion at 10 mg/kg.

引用

收藏

页码：1060 / 1064

页数：5

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