Design, synthesis and structure-activity relationship studies of hexahydropyrazinoquinolines as a novel class of potent and selective dopamine receptor 3 (D3) ligands.
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.
Ji
Min
M
Department of Internal Medicine, University of Michigan, CCGC/3316, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0934, USA.
Chen
Jianyong
J
Ding
Ke
K
Wu
Xihan
X
Varady
Judith
J
Levant
Beth
B
Wang
Shaomeng
S
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
C493595:Drd3 protein, rat; D008024:Ligands; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3