Predictive 3D‐Quantitative Structure‐Activity Relationship for A1 and A2A Adenosine Receptor Ligands

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AbstractThe use of QSAR applications to develop adenosine receptor (AR) antagonists is not so common. A library of all xanthine derivatives, obtained at the Department of Technology and Biotechnology of Drugs, was created. Sixty‐three active adenosine A1 receptor ligands and one hundred thirty nine active adenosine A2A receptor ligands were used for 3D‐QSAR investigation. The 3D‐QSAR equations with a high predictive power in estimating the binding affinity values of potential A1 and A2A ARs ligands were derived. For the first time, hybrid shape‐property descriptors were used in 3D‐QSAR for xanthine ARs ligands. The obtained models were characterized by a high regression and cross‐validation coefficients. Two types of the model validation were tested – dividing the library into the training set for model development and external set for model validation and increasing the number of library components and checking the model by cross‐validated regression coefficient. The analysis of the results depicts that for the A1 AR binding activity it is important for ligands to possess R1‐propyl substituents along with the phenyl or benzyl substituents bearing halogen atom and phenethyl moiety. For A2A AR affinity it could be favorable to introduce phenethyl or phenyl substituent connected with the tricyclic ring by the alkoxy chain. The nature of R1 group may not significantly affect the A2A AR affinity. High predictive power of the equations suggests their use for further development of adenosine receptor antagonists within xanthine derivatives.