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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 ?M against D1, D2S, D2L, D3, and D5). Further in vivo studies showed that ML398 reversed cocaine-induced hyperlocomotion at 10 mg/kg.

SUBMITTER: Berry CB

PROVIDER: S-EPMC4160761 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Berry Cynthia B CB Bubser Michael M Jones Carrie K CK Hayes John P JP Wepy James A JA Locuson Charles W CW Daniels J Scott JS Lindsley Craig W CW Hopkins Corey R CR

ACS medicinal chemistry letters 20140709 9

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 studie ...[more]

PMID: 25221667

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