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. 2008 Dec;4(4):287-303.
doi: 10.1007/s11302-008-9097-z. Epub 2008 Apr 29.

Recent improvements in the development of A(2B) adenosine receptor agonists

Pier Giovanni Baraldi  1 , Mojgan Aghazadeh Tabrizi, Francesca Fruttarolo, Romeo Romagnoli, Delia Preti
Affiliations

Recent improvements in the development of A(2B) adenosine receptor agonists

Pier Giovanni Baraldi et al. Purinergic Signal. 2008 Dec.

Abstract

Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A(1), A(2A), A(2B) and A(3) (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A(2B) AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A(2B) AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A(2B) AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N (6)-, C(2)-positions of the purine heterocycle and/or at the 5'-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N'-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-beta-D-ribofuranuronamide (19, hA(1) K (i) = 1050 nM, hA(2A) K (i) = 1550 nM, hA(2B) EC(50) = 82 nM, hA(3) K (i) > 5 muM) and its 2-chloro analogue 23 (hA(1) K (i) = 3500 nM, hA(2A) K (i) = 4950 nM, hA(2B) EC(50) = 210 nM, hA(3) K (i) > 5 muM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA(2B) AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60-6583, hA(1), hA(2A), hA(3) EC(50) > 10 muM; hA(2B) EC(50) = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis.

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Figures

Fig. 1
Fig. 1
Adenosine (1), NECA (2), N6-substituted-adenosine (3, 4) and NECA (5, 6) derivatives as nonselective A2B AR agonists
Fig. 2
Fig. 2
Dose-response curve of NECA and compound 19 on cAMP assays in hA2B AR CHO cells
Fig. 3
Fig. 3
2-Amino-4-(substituted)phenyl pyridine-3,5-dicarbonitrile derivatives: novel A2B AR agonists of particular interests for their potential therapeutic applications
Fig. 4
Fig. 4
Schematic overview of the most important structural modifications of adenosine and nonadenosine derivatives for a potent and/or selective activation of the A2B AR
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