title: Design, synthesis and structure-activity relationship studies of hexahydropyrazinoquinolines as a novel class of potent and selective dopamine receptor 3 (D3) ligands.
abstract: A hexahydropyrazinoquinoline (compound 5c) was previously discovered as a novel D3 ligand with a moderate binding affinity to the D3 receptor (Ki=304 nM) but no selectivity over the D1-like and D2-like receptors. In this study, we wish to report the design, synthesis and structure-activity relationship studies of a series of novel hexahydropyrazinoquinolines. Our efforts resulted in new compounds with improved binding affinity and selectivity. Among them, compound 12d has a Ki value of 2.6 nM for its binding affinity to the D3 receptor and has >2000- and 99-fold selectivity over the D1-like and D2-like receptors, respectively, representing a potent and selective D3 ligand.
authors.affiliation: Department of Internal Medicine, University of Michigan, CCGC/3316, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0934, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.forename: Xihan
authors.initials: X
authors.lastname: Wu
authors.forename: Judith
authors.initials: J
authors.lastname: Varady
authors.forename: Beth
authors.initials: B
authors.lastname: Levant
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D013329:Structure-Activity Relationship
chemical_list: C493595:Drd3 protein, rat; D008024:Ligands; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3