title: Enantiomerically pure hexahydropyrazinoquinolines as potent and selective dopamine 3 subtype receptor ligands.
abstract: We report the design and synthesis of a series of enantiomerically pure hexahydropyrazinoquinolines as potent and selective ligands for the dopamine 3 subtype receptor using a newly developed synthetic method and using in vitro pharmacological evaluation. Our efforts yielded optically pure ligands with high affinities for the D(3) receptor and outstanding selectivity over closely related D(1)-like and D(2)-like receptors. For example, compound 38a has a K(i) value of 5.7 nM to the D(3) receptor and selectivity greater than 10000- and 1600-fold over the D(1)-like and D(2)-like receptors, respectively, and thus is one of the most selective D(3) ligands reported to date.
authors.affiliation: Department of Internal Medicine and Medicinal Chemistry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0934, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.forename: Xihan
authors.initials: X
authors.lastname: Wu
authors.forename: Judith
authors.initials: J
authors.lastname: Varady
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.forename: Yipin
authors.initials: Y
authors.lastname: Lu
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Beth
authors.initials: B
authors.lastname: Levant
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C493595:Drd3 protein, rat; D008024:Ligands; D011719:Pyrazines; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3