Enantiomerically pure hexahydropyrazinoquinolines as potent and selective dopamine 3 subtype receptor ligands.
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.
Ding
Ke
K
Department of Internal Medicine and Medicinal Chemistry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0934, USA.
Chen
Jianyong
J
Ji
Min
M
Wu
Xihan
X
Varady
Judith
J
Yang
Chao-Yie
CY
Lu
Yipin
Y
Deschamps
Jeffrey R
JR
Levant
Beth
B
Wang
Shaomeng
S
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
C493595:Drd3 protein, rat; D008024:Ligands; D011719:Pyrazines; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3