Medicinal Chemistry and Pharmacology of A2B Adenosine Receptors

Author(s): Rosaria Volpini, Stefano Costanzi, Sauro Vittori, Gloria Cristalli, Karl-Norbert Klotz

Journal Name: Current Topics in Medicinal Chemistry

Volume 3 , Issue 4 , 2003

Become EABM
Become Reviewer
Call for Editor


The low affinity A2B adenosine receptor, like any other adenosine receptor subtype, belongs to the super-family of seven transmembrane domain G protein-coupled receptors (7TMs GPCR) and is classified by the GPCR database in the family of rhodopsin like receptors (Class A of GPCR). It has been cloned from various species, including rat and human, and its sequences are highly similar across species, ranging from 85% identity between human and mouse and 95% identity between rat and mouse. The A2B receptors show a ubiquitous distribution, the highest levels are present in cecum, colon and bladder, followed by blood vessels, lung, eye and mast cells. Through A2B receptors adenosine seems to cause mast cells degranulation, vasodilation, cardiac fibroblast proliferation, inhibition of Tumor Necrosis Factor (TNF-α), increased synthesis of interleukin-6 (IL-6), stimulation of Cl- secretion in intestinal epithelia and hepatic glucose production. Hence, A2B adenosine receptor agonists could be useful in the treatment of cardiac diseases like hypertension or myocardial infarction and in the management of septic shock, while antagonists may serve as novel drugs for asthma, Alzheimers disease, cystic fibrosis and type-II diabetes. No potent and selective A2B agonists have been reported so far, 5-N-ethylcarboxamidoadenosine (NECA) is one of the most active. The monosubstitution on N6-position of adenosine is well tolerated and that position appears to be a useful site for increasing A2B potency. Among substituents in 2-position of adenosine only 1- alkynyl chains are effective for A2B potency. In particular, the (S)-2-hydroxypropynyl substituents brought about the highest activity demonstrating that the A2B receptors discriminate between (R) and (S) diastereomers. Hence, (S)-2-phenylhydroxypropynylNECA (PHPNECA), with an EC50 = 0.22 μM, proved to be the most potent A2B agonist reported so far. Classical antagonists for adenosine receptors are alkylxanthines which show considerable potency at A2B receptors. Para substituted 1,3-dialkyl-8-phenylxanthines possess high affinity in binding assays, the 3- unsubstituted 1-alkyl analogues resulted more A2 B selective with the 8-[4-[(N-(2- hydroxyethyl)carboxamidomethyl)oxy]phenyl]-1-propylxanthine (60) showing the highest affinity (Ki = 1.2 nM) and selectivity (A1 / A2B = 60, A2A / A2B = 1,790, A3 / A2B = 360) . Among non-xanthine derivatives very promising are substituted purines, in which combination of appropriate substituents in 2-, 8-, and 9-position could lead to very potent and selective A2B antagonists.

Keywords: adenosine receptor, agonists, phpneca, antagonists, hypertension, asthma, alzheimer disease

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2003
Page: [427 - 443]
Pages: 17
DOI: 10.2174/1568026033392264
Price: $65

Article Metrics

PDF: 9