Comparative molecular field analysis (CoMFA) of a series of selective adenosine receptor A(2A) antagonists

Selective and potent antagonists for the A(2A) adenosine receptors have bee n described recently. The most potent compounds have a triazolo-pyrimidine structure, whereas 8-styryl-xanthines usually possess lower affinity at the A(2A) receptor. We have examined the quantitative structure activity relat ionships of 34 triazolo-pyrimidines using the Comparative Molecular Field A nalysis (CoMFA). The model developed accounts in a satisfactory manner for the structure-activity relationships within this series of A(2A) receptor a ntagonists (q(2) = 0.840, r(2) = 0.970) and, consequently, it can be used a s a guide in the design of novel analogs with optimized antagonistic activi ty. The overall predictivity of this model was tested on the published data of a set of external molecules giving acceptable results. The validity of the CoMFA approach as an effective tool for studying the 3D-QSAR of series of biologically active compounds is confirmed, even if additional efforts c learly are needed for trying to extend the models to structurally more vari ed series of derivatives. (C) 1999 Wiley-Liss, Inc.