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Identification of C10 nitrogen-containing aporphines with dopamine D1 versus D5 receptor selectivity.

Authors
  • Karki, Anupam1
  • Juarez, Reecan2
  • Namballa, Hari K2
  • Alberts, Ian3
  • Harding, Wayne W4
  • 1 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Ph.D. Program in Biochemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA.
  • 2 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA.
  • 3 LaGuardia Community College, Department of Chemistry, 31-10 Thompson Avenue, LIC, NY 11104, USA.
  • 4 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Ph.D. Program in Biochemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA; Ph.D. Program in Chemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA. Electronic address: [email protected]
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Apr 15, 2020
Volume
30
Issue
8
Pages
127053–127053
Identifiers
DOI: 10.1016/j.bmcl.2020.127053
PMID: 32107165
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT1A and 5-HT2A receptors and at human dopamine D1, D2 and D5 receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D5 receptor, thus attaining D1 versus D5 selectivity. Compound 20c was the most potent D1 ligand identified. Docking studies at D1 and D5 receptors indicate that the binding mode of 20c at the D1 receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D5 receptor, accounting for its D1 versus D5 selectivity. Considering the lack of affinity for the D5 receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of aporphines as sub-type selective D1 receptor tools. Copyright © 2020 Elsevier Ltd. All rights reserved.

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