Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Witt, Jonathan O.¹  McCollum, Andrea L.¹  Hurtado, Miguel A.²  Huseman, Eric D.¹  Jeffries, Daniel E.¹  Temple, Kayla J.¹  Plumley, Hyekyung C.^2,3  Blobaum, Anna L.^2,3  Lindsley, Craig W.^1,2,3  Hopkins, Corey R.^1,2,3 

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

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

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

关键词: Dopamine 4 receptor;    Antagonist;    Morpholine;    L-DOPA-induced dyskinesia;    Dopamine Selectivity;   

DOI  :  10.1016/j.bmcl.2016.03.102

来源: Elsevier

【 摘 要 】

Herein, we report the synthesis and structure-activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl)oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (<10% inhibition at 1 mu M against D-1, D-2L, D-2S, D-3, and D-5). (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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