Tranylcypromine Substitutedcis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D3Receptor Antagonists
Open Access
- 22 May 2014
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 57 (11) , 4962-4968
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.Keywords
Funding Information
- National Institutes of Health (R01 DA032943)
This publication has 32 references indexed in Scilit:
- Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclo- propyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydro-imidazo[1,5-a]pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 2Bioorganic & Medicinal Chemistry Letters, 2011
- CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full AgonistACS Medicinal Chemistry Letters, 2011
- Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective AntagonistScience, 2010
- Exploration of the Amine Terminus in a Novel Series of 1,2,4-Triazolo-3-yl-azabicyclo[3.1.0]hexanes as Selective Dopamine D3Receptor AntagonistsJournal of Medicinal Chemistry, 2010
- Current perspectives on selective dopamine D3receptor antagonists as pharmacotherapeutics for addictions and related disordersAnnals of the New York Academy of Sciences, 2010
- Dopamine D2, D3, and D4Selective Phenylpiperazines as Molecular Probes To Explore the Origins of Subtype Specific Receptor BindingJournal of Medicinal Chemistry, 2009
- N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor AntagonistsJournal of Medicinal Chemistry, 2009
- Design, synthesis and structure–activity relationship studies of hexahydropyrazinoquinolines as a novel class of potent and selective dopamine receptor 3 (D3) ligandsBioorganic & Medicinal Chemistry Letters, 2005
- Stereoselectivity and generality of the palladium-catalysed cyclopropanation of α,β-unsaturated carboxylic acids derivatized with Oppolzer's sultamJournal of the Chemical Society, Perkin Transactions 1, 1994
- Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reactionBiochemical Pharmacology, 1973