Discovery and characterization of ML398, a potent and selective antagonist of the D4 receptor with in vivo activity

Cynthia B. Berry; Michael Bubser; Carrie K. Jones; John P. Hayes; James A. Wepy; Charles W. Locuson; J. Scott Daniels; Craig W. Lindsley; Corey R. Hopkins

doi:10.1021/ml500267c

Discovery and characterization of ML398, a potent and selective antagonist of the D₄ receptor with in vivo activity

Cynthia B. Berry, Michael Bubser, Carrie K. Jones, John P. Hayes, James A. Wepy, Charles W. Locuson, J. Scott Daniels, Craig W. Lindsley, Corey R. Hopkins

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

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, D_2S, D_2L, D₃, and D₅). Further in vivo studies showed that ML398 reversed cocaine-induced hyperlocomotion at 10 mg/kg.

Original language	English (US)
Pages (from-to)	1060-1064
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	5
Issue number	9
DOIs	https://doi.org/10.1021/ml500267c
State	Published - Sep 11 2014
Externally published	Yes

Keywords

Dopamine 4 receptor antagonist
ML398
MLPCN
addiction

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1021/ml500267c

Cite this

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title = "Discovery and characterization of ML398, a potent and selective antagonist of the D4 receptor with in vivo activity",

abstract = "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 Ki = 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.",

keywords = "Dopamine 4 receptor antagonist, ML398, MLPCN, addiction",

author = "Berry, {Cynthia B.} and Michael Bubser and Jones, {Carrie K.} and Hayes, {John P.} and Wepy, {James A.} and Locuson, {Charles W.} and Daniels, {J. Scott} and Lindsley, {Craig W.} and Hopkins, {Corey R.}",

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AU - Berry, Cynthia B.

AU - Bubser, Michael

AU - Jones, Carrie K.

AU - Hayes, John P.

AU - Wepy, James A.

AU - Locuson, Charles W.

AU - Daniels, J. Scott

AU - Lindsley, Craig W.

AU - Hopkins, Corey R.

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AB - 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 Ki = 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.

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