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

  • ACS Med Chem Lett. 2014 Jul 9;5(9):1060-4. doi: 10.1021/ml500267c.
Cynthia B Berry  1 ,  Michael Bubser  2 ,  Carrie K Jones  2 ,  John P Hayes  3 ,  James A Wepy  3 ,  Charles W Locuson  4 ,  J Scott Daniels  4 ,  Craig W Lindsley  5 ,  Corey R Hopkins  5
Affiliations
  • 1. Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States ; Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, Tennessee 37232, United States.
  • 2. Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
  • 3. Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States ; Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
  • 4. Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, Tennessee 37232, United States ; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
  • 5. Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States ; Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, Tennessee 37232, United States ; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
PMID: 25221667 DOI: 10.1021/ml500267c
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, 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.
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