title: 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).
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
authors.forename: Jonathan O
authors.initials: JO
authors.lastname: Witt
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: McCollum
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Hurtado
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Huseman
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Jeffries
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Temple
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Hyekyung C
authors.initials: HC
authors.lastname: Plumley
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Electronic address: corey.r.hopkins@vanderbilt.edu.
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
mesh_terms: D000818:Animals; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D009025:Morpholines / Q000737:chemistry*; D051381:Rats; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D018492:Dopamine Antagonists; D009025:Morpholines; D050638:Receptors, Dopamine D4
keywords: Antagonist; Dopamine 4 receptor; Dopamine Selectivity; L-DOPA-induced dyskinesia; Morpholine