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 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.
authors.affiliation: 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.
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Berry
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Bubser
authors.affiliation: 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.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States ; Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Hayes
authors.affiliation: Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States ; Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Wepy
authors.affiliation: 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.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Locuson
authors.affiliation: 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.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: 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.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: 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.
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
keywords: Dopamine 4 receptor antagonist; ML398; MLPCN; addiction