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The Length and Flexibility of the 2‐Substituent of 9‐Ethyladenine Derivatives Modulate Affinity and Selectivity for the Human A 2A Adenosine Receptor
Author(s) -
Thomas Ajiroghene,
Buccioni Michela,
Dal Ben Diego,
Lambertucci Catia,
Marucci Gabriella,
Santinelli Claudia,
Spinaci Andrea,
Kachler Sonja,
Klotz KarlNorbert,
Volpini Rosaria
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500595
Subject(s) - chemistry , substituent , selectivity , adenosine receptor , stereochemistry , adenosine , receptor , biochemistry , agonist , catalysis
The A 2A adenosine receptor (A 2A AR) is a key target for the development of pharmacological tools for the treatment of central nervous system disorders. Previous works have demonstrated that the insertion of substituents at various positions on adenine leads to A 2A AR antagonists with affinity in the micromolar to nanomolar range. In this work, a series of 9‐ethyladenine derivatives bearing phenylalkylamino, phenylakyloxy or phenylakylthio groups of different lengths at the 2‐position were synthesised and tested against the human adenosine receptors. The derivatives showed sub‐micromolar affinity for these membrane proteins. The further introduction of a bromine atom at the 8‐position has the effect of improving the affinity and selectivity for all ARs and led to compounds that are able bind to the A 2A AR subtype at low nanomolar levels. Functional studies confirmed that the new adenine derivatives behave as A 2A AR antagonists with half‐maximal inhibitory concentration values in the nanomolar range. Molecular modelling studies provide a description of the possible binding mode of these compounds at the A 2A AR and an interpretation of the affinity data at this AR subtype.