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

Chen J, Levant B, Jiang C, Keck TM, Newman AH, Wang S - J. Med. Chem. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.

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.

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Chemicalstructures and absolute configurations of the novel compounds.
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fig3: Chemicalstructures and absolute configurations of the novel compounds.

Mentions: Among potential “head”groups under consideration,we found that tranylcypromine (8, Figure 3) was attractive because, like pramipexole (1) and 7, it contains a structurally rigid phenethylaminemoiety. Because the affinities of tranylcypromine for the dopaminereceptors are not known, we first tested the commercially available,racemic tranylcypromine in our dopamine receptor binding assays usingrat brain.23,24 Our data showed that tranylcyprominehas a weak affinity for the D3 receptor with a Ki value = 12.8 μM and displays 4-foldselectivity over the D2 receptor (Table 1). Although tranylcypromine is a weak D3 ligandand has a very limited selectivity over the D2 receptor,it was used as a starting point for our SAR study, which has ultimatelyyielded a class of potent and selective D3 antagonists.


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

Chen J, Levant B, Jiang C, Keck TM, Newman AH, Wang S - J. Med. Chem. (2014)

Chemicalstructures and absolute configurations of the novel compounds.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216217&req=5

fig3: Chemicalstructures and absolute configurations of the novel compounds.
Mentions: Among potential “head”groups under consideration,we found that tranylcypromine (8, Figure 3) was attractive because, like pramipexole (1) and 7, it contains a structurally rigid phenethylaminemoiety. Because the affinities of tranylcypromine for the dopaminereceptors are not known, we first tested the commercially available,racemic tranylcypromine in our dopamine receptor binding assays usingrat brain.23,24 Our data showed that tranylcyprominehas a weak affinity for the D3 receptor with a Ki value = 12.8 μM and displays 4-foldselectivity over the D2 receptor (Table 1). Although tranylcypromine is a weak D3 ligandand has a very limited selectivity over the D2 receptor,it was used as a starting point for our SAR study, which has ultimatelyyielded a class of potent and selective D3 antagonists.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.

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.

Show MeSH