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

A Concise Stereoselective Synthesis of (R)‐2‐Benzylmorpholine and ML398 from (R)‐(−)‐2‐Phenylglycinol

“…C2‐substituted morpholines are important structural cores present in many natural or synthetic compounds that exhibit interesting biological activities . For example, the ( R )‐2‐benzylmorpholine, a potent appetite suppressant drug , has also proven to be useful in the treatment of diabetes and cognitive disorders ; ML398, a potent and selective dopamine receptor antagonist (D4R), shows activity ( in vivo ) to reverse hyperlocomotion induced by cocaine (Figure ) . Interestingly, studies in the biological activities of ( R )‐2‐benzyl morpholine and ML398 have shown that the ( R )‐enantiomers are the active isomers.…”

“…Interestingly, studies in the biological activities of ( R )‐2‐benzyl morpholine and ML398 have shown that the ( R )‐enantiomers are the active isomers. To date, several methods for the preparation of ( R )‐2‐benzylmorpholine have been reported, including chemoenzymatic methodologies , resolution with dibenzoyl‐ l ‐tartaric acid , as well as asymmetric synthesis based on α‐aminooxylation or Sharpless epoxidation , while ML398 has been obtained by asymmetric synthesis based on an organocatalytic α‐chlorination of aldehydes .…”

Homology modeling, molecular dynamic simulation, and docking based binding site analysis of human dopamine (D4) receptor

“…However, most of these compounds indicated weak affinities toward D4 receptor [8,9]. ML398 has been presented as a selective D4 antagonist in recent studies [10]. Moreover, some selective ligands exhibited remarkable binding affinity to 5HT 1A R ,5HT 2A R, and 5HT 2B R [11,12].…”

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

“…1). 9,10 ML398 was active in vivo; however, the SAR analysis was limited due to the synthetic feasibility of modification of the upper right-hand phenethyl group. Thus, we wanted to evaluate alternative linker groups in order to more fully explore the SAR around both the N -linked groups as well as moieties adjacent to the oxygen group of the morpholine.…”

“…The 4-chlorobenzyl, 4a , direct comparator to ML398 ( K i = 36 nM) was equipotent to its predecessor compound ( K i = 42 nM) and the introduction of an ether linker led to a significant improvement (lowering) of the c Log P (5.10 vs. 3.73). 10 Further substitution around the benzyl group led to a more active compound (3,4-dimethyl, 4b , K i = 12.3 nM). Additional steric bulk was well tolerated as the naphthyl group was active as well ( 4d , K i = 17.8 nM).…”