title: Design, synthesis, and evaluation of hexahydrobenz[f]isoquinolines as a novel class of dopamine 3 receptor ligands.
abstract: We previously identified hexahydrobenz[f]isoquinoline (4a) as a new class of dopamine 3 receptor (D(3)) ligand. Herein, we described the design, synthesis, and preliminary structure-activity relationships of new analogues of 4a as a novel class of D(3) ligands. Among these new analogues, compound 4 h is a potent D(3) ligand (K(i)=6.1 nM) and has a selectivity of 133-fold between D(3)- and D(2)-like receptors, and of 163-fold between D(3)- and D(1)-like receptors, respectively. Thus, compound 4 h represents a promising new lead compound for further design and optimization toward achieving highly potent and selective D(3) ligands.
authors.affiliation: Departments of Internal Medicine and Medicinal Chemistry, University of Michigan, CCGC/3316, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0934, USA.
authors.forename: Xihan
authors.initials: X
authors.lastname: Wu
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Ji
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; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000378:metabolism*; D008024:Ligands; D008297:Male; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D013329:Structure-Activity Relationship
chemical_list: C493595:Drd3 protein, rat; D007546:Isoquinolines; D008024:Ligands; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3