Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity
3区 · 医学
作者: 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.
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.