Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists

Abstract

Herein, we report the synthesis and structure-activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl)oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (<10% inhibition at 1μM against D1, D2L, D2S, D3, and D5).

Keywords: Antagonist; Dopamine 4 receptor; Dopamine Selectivity; L-DOPA-induced dyskinesia; Morpholine.

Figure 1

Structure of previously disclosed chiral morpholine D₄ antagonist, ML398.

Figure 2

Metabolic soft-spot analysis of 5y in liver microsomes.

Scheme 1

Reagents and conditions: (a) CuI, Me₄Phen, Cs₂CO₃, toluene (14–30%); (b) ArOH, PPh₃, DIAD, benzene, rt (51%); (c) ArOH, PS-PPh₃, DIAD, THF, rt (21–25%); (d) ArOH, PPh₃, DIAD, THF, µW, 180 °C, 5 min (62%); (e) 4 M HCl in dioxanes; (f) polymer bound CNBH₃, R¹CHO, acetic acid, DCM (16–42%).