Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D(3) Receptor Antagonists

[Image: see text] We report a class of potent and selective dopamine D(3) receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D(3) 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...

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Autores principales: Chen, Jianyong, Levant, Beth, Jiang, Cheng, Keck, Thomas M., Newman, Amy Hauck, Wang, Shaomeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216217/
https://www.ncbi.nlm.nih.gov/pubmed/24848155
http://dx.doi.org/10.1021/jm401798r
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author Chen, Jianyong
Levant, Beth
Jiang, Cheng
Keck, Thomas M.
Newman, Amy Hauck
Wang, Shaomeng
author_facet Chen, Jianyong
Levant, Beth
Jiang, Cheng
Keck, Thomas M.
Newman, Amy Hauck
Wang, Shaomeng
author_sort Chen, Jianyong
collection PubMed
description [Image: see text] We report a class of potent and selective dopamine D(3) receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D(3) 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 D(3) receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D(2) receptors. Evaluation in a β-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D(3) receptor.
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spelling pubmed-42162172015-05-22 Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D(3) Receptor Antagonists Chen, Jianyong Levant, Beth Jiang, Cheng Keck, Thomas M. Newman, Amy Hauck Wang, Shaomeng J Med Chem [Image: see text] We report a class of potent and selective dopamine D(3) receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D(3) 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 D(3) receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D(2) receptors. Evaluation in a β-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D(3) receptor. American Chemical Society 2014-05-22 2014-06-12 /pmc/articles/PMC4216217/ /pubmed/24848155 http://dx.doi.org/10.1021/jm401798r Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Chen, Jianyong
Levant, Beth
Jiang, Cheng
Keck, Thomas M.
Newman, Amy Hauck
Wang, Shaomeng
Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D(3) Receptor Antagonists
title Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D(3) Receptor Antagonists
title_full Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D(3) Receptor Antagonists
title_fullStr Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D(3) Receptor Antagonists
title_full_unstemmed Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D(3) Receptor Antagonists
title_short Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D(3) Receptor Antagonists
title_sort tranylcypromine substituted cis-hydroxycyclobutylnaphthamides as potent and selective dopamine d(3) receptor antagonists
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216217/
https://www.ncbi.nlm.nih.gov/pubmed/24848155
http://dx.doi.org/10.1021/jm401798r
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