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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Arrestins / metabolism
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Cell Line
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Cyclobutanes / chemistry*
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Cyclobutanes / pharmacology
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Humans
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Male
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Naphthalenes / chemistry*
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Naphthalenes / pharmacology
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Radioligand Assay
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Rats, Sprague-Dawley
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Receptors, Dopamine D3 / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
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Tranylcypromine / analogs & derivatives*
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Tranylcypromine / chemistry*
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Tranylcypromine / pharmacology
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beta-Arrestins
Substances
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Arrestins
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Cyclobutanes
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N-(3-(2-((2-(4-chlorophenyl)cyclopropyl)(propyl)-amino)ethyl)-3-hydroxycyclobutyl)-2-naphthamide
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Naphthalenes
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Receptors, Dopamine D3
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beta-Arrestins
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Tranylcypromine