Frontiers in Medicinal Chemistry

Volume: 2

Indexed in: Scopus, EMBASE, Chemical Abstracts, EBSCO, Ulrich's Periodicals Directory.

Frontiers in Medicinal Chemistry is a book series devoted to the review of areas of important topical interest to medicinal chemists and others in allied disciplines. Frontiers in Medicinal Chemistry ...
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Potent and Selective A2A Adenosine Receptor Antagonists: Recent Improvement

Pp. 49-62 (14)

Barbara Cacciari, Giorgia Pastorin, Stefano Moro and Giampiero Spalluto


Due to the well known receptor-receptor interaction between adenosine A2A and dopamine D2 receptors in the basal ganglia, the discovery and development of potent and selective A2A adenosine receptor antagonists, became, in the last ten years, an attractive field of research to discovery new drugs for the treatment of neurodegenerative disorders, such as Parkinsons disease.

Different compounds have been investigated as A2A adenosine receptor antagonists, which could be classified in two great families: xanthine derivatives and nitrogen poliheterocyclic systems. These studies led to the discovery of some highly potent and selective A2A adenosine receptor antagonists such as ZM241385, SCH58261 and some xanthine derivatives (KW6002) which have been used as pharmacological tools for studying this receptor subtype.

Anyway most of the reported compounds showed some problems which do not permit their use in clinical studies, such as poor water solubility (SCH58261, and xanthine derivatives) or good affinity for other adenosine receptor subtypes (e.g. ZM241385 possess good affinity for A2B adenosine receptors).

Recently, a three-dimensional model of the human A2A adenosine receptor (AR) and its docked ligands was built by homology to rhodopsin and validated with sitedirected mutagenesis and the synthesis of chemically complementary agonists and antagonists. Interestingly, the molecular modeling results clearly delineated the interactions involved in the binding of agonists and antagonists, which correlated well with known experimental results.

The aim of this report is to briefly summarize the recent progress made in this attractive field of research.


Adenosine receptors, antagonists, xanthine derivatives, heterocyclic derivatives, neurodegenerative disorders


Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, Via Fossato di Mortasa 17/19, I-44100, Ferrara, Italy.