Tranylcypromine substituted cis-hydroxycyclobutylnaphthamides as potent and selective dopamine D₃ receptor antagonists.
We report a class of potent and selective dopamine D3 receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D3 receptor (K(i) = 12.8 μM), our efforts have yielded (1R,2S)-11 (CJ-1882), which has K(i) values of 2.7 and 2.8 nM at the rat and human dopamine D3 receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D2 receptors. Evaluation in a β-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D3 receptor.
Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
Jianyong
J
Chen
Beth
B
Levant
Cheng
C
Jiang
Thomas M
TM
Keck
Amy Hauck
AH
Newman
Shaomeng
S
Wang
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002460:Cell Line; D003503:Cyclobutanes / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D000071557:beta-Arrestins
D019390:Arrestins; D003503:Cyclobutanes; C000590792:N-(3-(2-((2-(4-chlorophenyl)cyclopropyl)(propyl)-amino)ethyl)-3-hydroxycyclobutyl)-2-naphthamide; D009281:Naphthalenes; D050637:Receptors, Dopamine D3; D000071557:beta-Arrestins; D014191:Tranylcypromine