The integration of ligand- and structure-based strategies might sensitively increase the success of drug discovery process. We have recently described the application of Molecular Electrostatic Potential autocorrelated vectors (autoMEPs) in generating both linear (Partial Least-Square, PLS) and nonlinear (Response Surface Analysis, RSA) 3D-QSAR models to quantitatively predict the binding affinity of human adenosine A3 receptor antagonists. Moreover, we have also reported a novel GPCR modeling approach, called Ligand-Based Homology Modeling (LBHM), as a tool to simulate the conformational changes of the receptor induced by ligand binding. In the present study, the application of both linear and nonlinear 3D-QSAR methods and LBHM computational techniques has been used to depict the hypothetical antagonist binding site of the human adenosine A2A receptor. In particular, a collection of 127 known human A2A antagonists has been utilized to derive two 3D-QSAR models (autoMEPs/PLS&RSA). In parallel, using a rhodopsin-driven homology modeling approach, we have built a model of the human adenosine A2A receptor. Finally, 3D-QSAR and LBHM strategies have been utilized to predict the binding affinity of five new human A2A pyrazolo-triazolo-pyrimidine antagonists finding a good agreement between the theoretical and the experimental predictions.
Some pyrazolotriazolopyrimidines bearing different heteroarylcarbamoylamino moieties at the N5-position are described. We previously reported the synthesis of a water soluble compound with high potency and selectivity versus the human A3 adenosine receptor as antagonist, and herein we present an enlarged series of compounds related to the previously mentioned one. These compounds showed A3 adenosine receptor affinity in the nanomolar range and different levels of selectivity evaluated in radioligand binding assays at human A1, A2A, A2B, and A3 adenosine receptors. In particular, the effect of the heteroaryl substituents at the N5 position has been analyzed. This study allows us to recognize that the presence of a pyridinium moiety in this position not only increases water solubility but also improves or retains potency and selectivity at the human A3 adenosine receptors. In contrast, replacement of pyridine with different heterocycles produces loss of affinity and selectivity at the human A3 adenosine receptors. A molecular modeling study has been carried out with the aim to explain these various binding profiles.
There are pharmacological evidences that A(2B) receptors are involved in inflammatory processes, such as asthma. For this reason, many efforts has been made for identifying selective A(2B) antagonists as anti-asthmatic agents. The updated material related to this field has been rationalised and arranged in order to offer an overview of the topic.
In the last few years, many efforts have been made to search for potent and selective human A 3 adenosine antagonists. In particular, one of the most promising human A 3 adenosine receptor antagonists is represented by the pyrazolo-triazolo-pyrimidine family. This class of compounds has been strongly investigated from the point of view of structure-activity relationships. In particular, it has been observed that fundamental requisites for having both potency and selectivity at the human A 3 adenosine receptors are the presence of a small substituent at the N 8 position and an unsubstitued phenyl carbamoyl moiety at the N 5 position. In this study, we report the role of the N 5 -bond type on the affinity and selectivity at the four adenosine receptor subtypes. The observed structureactivity relationships of this class of antagonists are also exhaustively rationalized using the recently published ligand-based homology modeling approach.
In the last 5 years, many efforts have been conducted searching potent and selective human A 3 adenosine antagonists. In this field several different classes of compounds, possessing very good affinity (nM range) and with a broad range of selectivity, have been proposed. Recently, our group synthesized a new series of pyrazolo-triazolo-pyrimidines bearing different substitutions at the N 5 and N 8 positions, which have been described as highly potent and selective human A 3 adenosine receptor antagonists. The present review summarizes available data and provides an overview of the structure-activity relationships found for this class of human A 3 adenosine receptor antagonists.
A new series of 2,6,9-trisubstituted adenines (5-14) have been prepared and evaluated in radioligand binding studies for their affinity at the human A 1 , A 2A and A 3 adenosine receptors and in adenylyl cyclase experiments for their potency at the human A 2B subtype. From this preliminary study the conclusion can be drawn that introduction of bulky chains at the N 6 position of 9-propyladenine significantly increased binding affinity at the human A 1 and A 3 adenosine receptors, while the presence of a chlorine atom at the 2 position resulted in a not univocal effect, depending on the receptor subtype and/or on the substituent present in the N 6 position. However, in all cases, the presence in the 2 position of a chlorine atom favoured the interaction with the A 2A subtype. These results demonstrated that, although the synthesized compounds were found to be quite inactive at the human A 2B subtype, adenine is a useful template for further development of simplified adenosine receptor antagonists with distinct receptor selectivity profiles.
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