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Lipid Trolling to Optimize A3 Adenosine Receptor-Positive Allosteric Modulators (PAMs).

Balaram Pradhan1, Matteo Pavan1, Courtney L Fisher2

  • 1Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States.

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Researchers developed novel positive allosteric modulators (PAMs) for the A3 adenosine receptor (A3AR). These compounds enhance A3AR agonist efficacy by targeting a unique lipid-exposed binding site, improving drug design strategies.

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Molecular Modeling

Background:

  • A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs) enhance agonist efficacy.
  • Previous A3AR PAMs showed limited allosteric effects due to concurrent orthosteric antagonism.
  • A putative lipid-exposed allosteric binding site on the cytosolic side was proposed.

Purpose of the Study:

  • To design and synthesize novel A3AR PAMs with improved allosteric activity.
  • To investigate the role of a lipid-exposed allosteric binding site in modulating A3AR function.
  • To explore structure-activity relationships for optimizing A3AR PAM efficacy.

Main Methods:

  • Mutagenesis and homology modeling to characterize the allosteric binding site.
  • Chemical synthesis and functionalization of the imidazo[4,5-c]quinolin-4-amine scaffold.
  • Functional assays ([35S]GTPγS binding) and molecular dynamics simulations.

Main Results:

  • Functionalization with linear alkyl-alkynyl chains bearing terminal cationic groups enhanced A3AR PAM activity.
  • Compound 26 (MRS8247) and its homologues increased the Emax and potency of the A3AR agonist Cl-IB-MECA.
  • Molecular dynamics simulations supported a 'lipid trolling' mechanism involving electrostatic anchoring to phospholipids.

Conclusions:

  • Rational design targeting an extrahelical, lipidic binding site significantly improved A3AR PAM activity.
  • The novel A3AR PAMs demonstrate potential for therapeutic applications.
  • The findings provide new insights into allosteric modulation mechanisms at G protein-coupled receptors.