A Series of 2,4-Disubstituted Quinolines as a New Class of Allosteric Enhancers of the Adenosine A3 Receptor | Zendy

Laura H. Heitman | Zendy; Anikó Göblyös | Zendy; Annelien J.M. Zweemer | Zendy; Renée Bakker | Zendy; Thea MulderKrieger | Zendy; Jacobus P. D. van Veldhoven | Zendy; Henk de Vries | Zendy; Johannes Brussee | Zendy; Adriaan P. IJzerman | Zendy

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A Series of 2,4-Disubstituted Quinolines as a New Class of Allosteric Enhancers of the Adenosine A₃ Receptor

Author(s) -

Laura H. Heitman,

Anikó Göblyös,

Annelien J.M. Zweemer,

Renée Bakker,

Thea MulderKrieger,

Jacobus P. D. van Veldhoven,

Henk de Vries,

Johannes Brussee,

Adriaan P. IJzerman

Publication year - 2009

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/jm8014052

Subject(s) - chemistry , allosteric regulation , enhancer , adenosine , class (philosophy) , adenosine receptor , series (stratigraphy) , stereochemistry , receptor , pharmacology , biochemistry , agonist , artificial intelligence , gene , biology , medicine , paleontology , gene expression , computer science

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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