Recent improvements in the development of A2B adenosine receptor agonists |
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Authors: | Pier Giovanni Baraldi Mojgan Aghazadeh Tabrizi Francesca Fruttarolo Romeo Romagnoli Delia Preti |
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Institution: | (1) Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via fossato di Mortara 17-19, 44100 Ferrara, Italy |
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Abstract: | Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named
A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B 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 A2B 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 A2B 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-, C2-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-β-D-ribofuranuronamide (19, hA1
K
i = 1050 nM, hA2A
K
i = 1550 nM, hA2B EC50 = 82 nM, hA3
K
i > 5 μM) and its 2-chloro analogue 23 (hA1
K
i = 3500 nM, hA2A
K
i = 4950 nM, hA2B EC50 = 210 nM, hA3
K
i > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay
in Chinese hamster ovary (CHO) cells expressing hA2B 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, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis.
This article has previously been published in issue 4/4, under doi:. |
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Keywords: | A2B adenosine receptor A2B AR agonist Atherosclerosis Coronary artery disease Cystic fibrosis Impotence Inflammation Myocardial infarction Septic shock |
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