2. Academic Validation
  3. A series of 2,4-disubstituted quinolines as a new class of allosteric enhancers of the adenosine A3 receptor

A series of 2,4-disubstituted quinolines as a new class of allosteric enhancers of the adenosine A3 receptor

  • J Med Chem. 2009 Feb 26;52(4):926-31. doi: 10.1021/jm8014052.
Laura H Heitman 1,  Anikó Göblyös,  Annelien M Zweemer,  Renée Bakker,  Thea Mulder-Krieger,  Jacobus P D van Veldhoven,  Henk de Vries,  Johannes Brussee,  Adriaan P Ijzerman
Affiliations

Affiliation

  • 1 Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
PMID: 19161279 DOI: 10.1021/jm8014052
Abstract

The Adenosine Receptor subfamily consists of the adenosine A(1), A(2A), A(2B), and A(3) receptors, which are localized in a variety of tissues throughout the human body. It is, therefore, a challenge to develop receptor specific ligands with improved tissue selectivity. Allosteric modulators could have these therapeutic advantages over orthosteric ligands. In the present study, a series of 2,4-disubstituted quinolines were synthesized on the basis of the structure of LUF6000 (34). Compound 27 (LUF6096) was able to allosterically enhance agonist binding to a similar extent as 34. In addition, this new compound showed low, if any, orthosteric affinity for any of the adenosine receptors. In a functional assay, compound 27 showed improved activity in comparison to 34, as it increased both the intrinsic efficacy and the potency of the reference agonist Cl-IB-MECA at the human adenosine A(3) receptor.

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