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

ACS Med Chem Lett. 2014 Jul 9;5(9):1060-4. doi: 10.1021/ml500267c. eCollection 2014 Sep 11.

Authors

Cynthia B Berry¹, Michael Bubser², Carrie K Jones², John P Hayes³, James A Wepy³, Charles W Locuson⁴, J Scott Daniels⁴, Craig W Lindsley⁵, Corey R Hopkins⁵

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.

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.

Grants and funding

T32 GM065086/GM/NIGMS NIH HHS/United States