Organic, Medicinal and Pharmaceutical Chemist
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J Med Chem Article: Adenine based acyclic-nucleotides as novel P2X3 receptor ligands
Jul 1st
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Adenine based acyclic-nucleotides as novel P2X3 receptor ligands
Volpini Rosaria; Mishra, RC; Kachare DD; Dalben Diego; Catia Lambertucci; Ippolito Antonini; Vittori sauro; Marucci Gabriella and Nistri Andrea
Abstract:
A new series of acyclic nucleotides based on the adenine skeleton and bearing in 9-position a phosphorylated four carbon chain has been synthesized. Various substituents were introduced in 2-position of the adenine core. The new compounds were evaluated on rat P2X3 receptors, using patch clamp recording from HEK transfected cells and the full P2X3 agonist α,β-meATP as reference compound. The results suggest that certain acyclic nucleotides, in particular compounds 28 and 29, are endowed with modest partial agonism on P2X3 receptors. This is an interesting property that can depress the function of P2X3 receptors, whose activation is believed to be involved in a number of chronic pain conditions including neuropathic pain and migraine. In fact, the new acyclic nucleotides are able to persistently block (by desensitization) P2X3 receptor activity after a brief, modest activation, yet leaving the ability of sensory neurons to mediate responses to standard painful stimuli via a lower level of signaling.
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CHEM MED CHEM Article: Adenosine A2A Receptor Antagonists: New 8-Substituted 9-Ethyladenines as Tools for in vivo Rat Models of Parkinson’s Disease
Jun 24th
Adenosine A2A Receptor Antagonists: New 8-Substituted 9-Ethyladenines as Tools for in vivo Rat Models of Parkinson’s Disease
Rosaria Volpini, Prof., Diego Dal Ben, Dr., Catia Lambertucci, Dr., Gabriella Marucci, Prof. Dr., Ram Chandra Mishra, Dr., Anna Teresa Ramadori, Dr., Karl-Norbert Klotz, Prof., Maria Letizia Trincavelli, Dr. , Claudia Martini, Prof., Gloria Cristalli, Prof.
Abstract:
A new series of 8-substituted 9-ethyladenine derivatives has been synthesized and tested at rat and human adenosine receptors. Binding data demonstrates that some compounds could represent new tools suitable for in vivo studies in rat models of Parkinson’s disease and for the design of new molecules with improved affinity and selectivity at human AA2AR.
Clinical evidence has demonstrated that AA2AR antagonists could be an alternative approach to the treatment of Parkinson’s disease. Recently, three 9-ethyladenine derivatives bearing a bromine atom, an ethoxy group, and a furyl ring, respectively, in the 8-position have been reported to ameliorate motor deficits in rat Parkinson’s disease models, suggesting a potential therapeutic role for these compounds. Starting from these observations, a new series of 9-ethyladenine derivatives, bearing different substituents such as halogens, alkoxy groups, aromatic and heteroaromatic rings in the 8-position, were synthesized. Radioligand binding assays demonstrated that some of the new compounds bind rat AA2AR with higher affinity than the previously reported congeners and that there is a good correlation between binding to rat and human receptors. Hence, the new molecules could represent new tools suitable for the in vivo studies in rat models of Parkinson’s disease. Finally, a molecular docking analysis of the compounds was performed using a homology model of rat AA2AR, built using the human crystal structure as the template, and results are in agreement with the binding data.
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