Design, synthesis, biological evaluation, and comparative docking study of 1,2,4-triazolones as CB1 receptor selective antagonists

Abstract Cannabinoids are potentially useful for the treatment of several diseases. In the present work, we report the syntheses and biological evaluations of 1,2,4-triazolone derivatives designed using a combined approach of scaffold hopping and pharmacophore-oriented method. These compounds exhibited interesting antagonistic activity to the cannabinoid CB1 receptor. The preliminary structure–activity relationships were further discussed. In addition, docking simulations were performed on the good bioactive compound 5c and the low potent compound 5d , respectively, on the basis of homology models of the CB1 and CB2 receptors, which were constructed based on human β2-adrenoreceptor and optimized in a membrane environment by MD simulations. Calculation of the binding modes gave us insights into the structural requirements for improving the cannabinoid receptor bioactivity and selectivity.