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Synthesis of novel and functionally selective non-competitive muscarinic antagonists as chemical probes.

Authors
  • Boulos, John F1
  • Jakubik, Jan2
  • Boulos, John M3
  • Randakova, Alena2
  • Momirov, Jelena1
  • 1 Department of Physical Sciences, Barry University, Miami Shores, FL, USA.
  • 2 Department of Neurochemistry, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic. , (Czechia)
  • 3 Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
Type
Published Article
Journal
Chemical Biology & Drug Design
Publisher
Wiley (Blackwell Publishing)
Publication Date
Jan 01, 2018
Volume
91
Issue
1
Pages
93–104
Identifiers
DOI: 10.1111/cbdd.13059
PMID: 28646631
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Muscarinic receptors are known to play important biological roles and are drug targets for several human diseases. In a pilot study, novel muscarinic antagonists were synthesized and used as chemical probes to obtain additional information of the muscarinic pharmacophore. The design of these ligands made use of current orthosteric and allosteric models of drug-receptor interactions together with chemical motifs known to achieve muscarinic receptor selectivity. This approach has led to the discovery of several non-competitive muscarinic ligands that strongly bind at a secondary receptor site. These compounds were found to be non-competitive antagonists that completely abolished carbachol activation in functional assays. Several of these compounds antagonized functional response to carbachol with great potency at M1 and M4 than at the rest of receptor subtypes. © 2017 John Wiley & Sons A/S.

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