Studies of Phenylethynyl-pyrrolo[1,2-a]pyrazine as mGluR5 Antagonists Using 3D-QSAR Method

Abstract

In recent years, interest has been paid in development of compounds with high biological activity for metabotropic glutamate receptors (mGluRs), an interesting therapeutic target in the treatment of cocaine seeking behaviour. In the present work, based on a data set of 84 collected phenylethynylpyrrolo[ 1,2-a]pyrazine mGluR5 antagonists with diverse kinds of structures, a variety of in silico modeling approaches including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA) were carried out to reveal the requisite 3D structural features for activity. Present results show that both the optimal ligand-based CoMFA (Q² = 0.53, R² _ncv = 0.92, R² _pre = 0.80, SEE = 0.26, SEP = 0.44) and CoMSIA (Q² = 0.51, R² _ncv = 0.85, R² _pre = 0.80, SEE = 0.36, SEP = 0.42) models are reliable with proper predictive capacity. In addition, the analysis about the CoMFA and CoMSIA contour maps shows that: (1) Electropositive groups in Ar substituent are beneficial to enhance the activity; (2) R substituent with HB acceptor also leads to high activity; (3) Bulky R and Ar substituents are not favoured in mGluR5; (4) R substituent with hydrophilic group can improve the biological activity. All these results might provide information for better understanding of the mechanism of antagonism and thus be helpful in design of new potent mGluR5 antagonists.