title: Discovery, optimization, and characterization of novel D2 dopamine receptor selective antagonists.
abstract: The D2 dopamine receptor (D2 DAR) is one of the most validated drug targets for neuropsychiatric and endocrine disorders. However, clinically approved drugs targeting D2 DAR display poor selectivity between the D2 and other receptors, especially the D3 DAR. This lack of selectivity may lead to undesirable side effects. Here we describe the chemical and pharmacological characterization of a novel D2 DAR antagonist series with excellent D2 versus D1, D3, D4, and D5 receptor selectivity. The final probe 65 was obtained through a quantitative high-throughput screening campaign, followed by medicinal chemistry optimization, to yield a selective molecule with good in vitro physical properties, metabolic stability, and in vivo pharmacokinetics. The optimized molecule may be a useful in vivo probe for studying D2 DAR signal modulation and could also serve as a lead compound for the development of D2 DAR-selective druglike molecules for the treatment of multiple neuropsychiatric and endocrine disorders.
authors.affiliation: Discovery Innovation, NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Xiao
authors.forename: R Benjamin
authors.initials: RB
authors.lastname: Free
authors.forename: Elena
authors.initials: E
authors.lastname: Barnaeva
authors.forename: Jennie L
authors.initials: JL
authors.lastname: Conroy
authors.forename: Trevor
authors.initials: T
authors.lastname: Doyle
authors.forename: Brittney
authors.initials: B
authors.lastname: Miller
authors.forename: Marthe
authors.initials: M
authors.lastname: Bryant-Genevier
authors.forename: Mercedes K
authors.initials: MK
authors.lastname: Taylor
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.forename: Andrés E
authors.initials: AE
authors.lastname: Dulcey
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.forename: Steve
authors.initials: S
authors.lastname: Titus
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: David R
authors.initials: DR
authors.lastname: Sibley
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
mesh_terms: D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D055808:Drug Discovery; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists