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

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

Berry CB¹, Bubser M², Jones CK², Hayes JP³, Wepy JA³, Locuson CW⁴, Daniels JS⁴, Lindsley CW⁵, Hopkins CR⁵.

Author information

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.