Tranylcypromine substituted cis -hydroxycyclobutylnaphthamides as potent and selective dopamine D3 receptor antagonists

Jianyong Chen; Beth Levant; Cheng Jiang; Thomas M. Keck; Amy Hauck Newman; Shaomeng Wang

doi:10.1021/jm401798r

Tranylcypromine substituted cis -hydroxycyclobutylnaphthamides as potent and selective dopamine D₃ receptor antagonists

Jianyong Chen, Beth Levant, Cheng Jiang, Thomas M. Keck, Amy Hauck Newman, Shaomeng Wang

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	4962-4968
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	11
DOIs	https://doi.org/10.1021/jm401798r
State	Published - Jun 12 2014
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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title = "Tranylcypromine substituted cis -hydroxycyclobutylnaphthamides as potent and selective dopamine D3 receptor antagonists",

abstract = "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 (Ki = 12.8 μM), our efforts have yielded (1R,2S)-11 (CJ-1882), which has Ki 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.",

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AU - Chen, Jianyong

AU - Levant, Beth

AU - Jiang, Cheng

AU - Keck, Thomas M.

AU - Newman, Amy Hauck

AU - Wang, Shaomeng

PY - 2014/6/12

Y1 - 2014/6/12

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AB - 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 (Ki = 12.8 μM), our efforts have yielded (1R,2S)-11 (CJ-1882), which has Ki 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.

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Tranylcypromine substituted cis -hydroxycyclobutylnaphthamides as potent and selective dopamine D₃ receptor antagonists

Abstract

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