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

Herein, we report the structure–activity relationship of a chiral morpholine-based scaffold, which led to the identification of a potent and selective dopamine 4 (D4) receptor antagonist. The 4-chlorobenzyl moiety was identified, and the compound was designated an MLPCN probe molecule, ML398. ML398...

Full description

Saved in:

Bibliographic Details
Published in:	ACS medicinal chemistry letters Vol. 5; no. 9; pp. 1060 - 1064
Main Authors:	Berry, Cynthia B, Bubser, Michael, Jones, Carrie K, Hayes, John P, Wepy, James A, Locuson, Charles W, Daniels, J. Scott, Lindsley, Craig W, Hopkins, Corey R
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 11-09-2014
Subjects:	Letter ML398 MLPCN Dopamine 4 receptor antagonist addiction
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Herein, we report the structure–activity relationship of a chiral morpholine-based scaffold, which led to the identification of a potent and selective dopamine 4 (D4) receptor antagonist. The 4-chlorobenzyl moiety was identified, and the compound was designated an MLPCN probe molecule, ML398. ML398 is potent against the D4 receptor with IC50 = 130 nM and K i = 36 nM and shows no activity against the other dopamine receptors tested (>20 μM against D1, D2S, D2L, D3, and D5). Further in vivo studies showed that ML398 reversed cocaine-induced hyperlocomotion at 10 mg/kg.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This paper was published ASAP on July 15, 2014. The abstract graphic was corrected and the revised version was reposted on July 16, 2014.
ISSN:	1948-5875 1948-5875
DOI:	10.1021/ml500267c