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Abstract
Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1, A2A, A2B and A3, which belong to the G-protein-coupled receptor superfamily. The human A3AR (hA3AR) subtype is implicated in several cytoprotective functions. Therefore, hA3AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anti-cancer and cardioprotective agents. Here, we prepared novel adenosine derivatives with indole moiety as hA3AR ligands. According to the biological assay, we found that 2-substituents 11 were critical structural determinants for A3AR ligands (Ki = 111 nM). The observed structure–affinity relationships of this class of ligands were also exhaustively rationalized using the molecular modelling approach. This allows the investigation on the binding mode of the potential compound in the ligand-binding pocket of the human A3 receptor. The results demonstrated that 11 can interact with the ASN250, GLN167, PHE168 and VAL178 through hydrogen bonding, which are shown to be important for ligand–receptor interaction.
Highlights
Adenosine is an endogenous purine nucleoside that modulates many physiological processes, which is composed of a molecule of adenine attached to a ribose sugar molecule moiety2018 The Authors
Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1, A2A, A2B and A3, which belong to the G-protein-coupled receptor superfamily
The human A3AR subtype is implicated in several cytoprotective functions
Summary
Adenosine is an endogenous purine nucleoside that modulates many physiological processes, which is composed of a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety2018 The Authors. Adenosine is widely found in nature and plays an important role 2 in biochemical processes, such as energy transfer as adenosine triphosphate (ATP) and adenosine diphosphate (ADP), as well as in signal transduction as cyclic adenosine monophosphate (cAMP). It is a neuromodulator, believed to play a role in promoting sleep and suppressing arousal. The four receptor subtypes are further classified based on their ability to either stimulate or inhibit adenylate cyclase activity They have long been considered to be promising therapeutic targets in a wide range of conditions, ranging from cerebral diseases to cancer, including inflammatory and immunological disorders [8,9]. Encouraging results have emerged with AR ligands for the management of several physiological conditions in preclinical and clinical settings [7,10]
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