title: Highlights on the development of A(2A) adenosine receptor agonists and antagonists.
abstract: Although significant progress has been made in the past few decades demonstrating that adenosine modulates a variety of physiological and pathophysiological processes through the interaction with four subtypes of a family of cell-surface G-protein-coupled receptors, clinical evaluation of some adenosine receptor ligands has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, or a lack of effects, in some cases perhaps due to receptor desensitization or to low receptor density in the targeted tissue. Currently, three A(2A) adenosine receptor agonists have begun phase III studies. Two of them are therapeutically evaluated as pharmacologic stress agents and the third proved to be effective in the treatment of acute spinal cord injury (SCI), while avoiding the adverse effects of steroid agents. On the other hand, the great interest in the field of A(2A) adenosine receptor antagonists is related to their application in neurodegenerative disorders, in particular, Parkinson's disease, and some of them are currently in various stages of evaluation. This review presents an update of medicinal chemistry and molecular recognition of A(2A) adenosine receptor agonists and antagonists, and stresses the strong need for more selective ligands at the A(2A) human subtype.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy. gloria.cristalli@unicam.it
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristalli
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D015195:Drug Design; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D043562:Receptors, G-Protein-Coupled; D000241:Adenosine