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 journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1060-1064
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume5
Issue number9
DOIs
StatePublished - Sep 11 2014

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Dopamine Antagonists
Dopamine Receptors
Dopamine
Structure-Activity Relationship
Cocaine
Scaffolds
Inhibitory Concentration 50
Molecules
morpholine

Keywords

  • Dopamine 4 receptor antagonist
  • ML398
  • MLPCN
  • addiction

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

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

In: ACS Medicinal Chemistry Letters, Vol. 5, No. 9, 11.09.2014, p. 1060-1064.

Research output: Contribution to journalArticle

Berry, CB, Bubser, M, Jones, CK, Hayes, JP, Wepy, JA, Locuson, CW, Daniels, JS, Lindsley, CW & Hopkins, CR 2014, 'Discovery and characterization of ML398, a potent and selective antagonist of the D4 receptor with in vivo activity', ACS Medicinal Chemistry Letters, vol. 5, no. 9, pp. 1060-1064. https://doi.org/10.1021/ml500267c
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. / Discovery and characterization of ML398, a potent and selective antagonist of the D4 receptor with in vivo activity. In: ACS Medicinal Chemistry Letters. 2014 ; Vol. 5, No. 9. pp. 1060-1064.
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