Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB R Ligands.

Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline-2,4(1H,3H)-diones as CB R-selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB R in calcium mobilization assays, and four displayed CB R agonist activity, with EC values below 30 nm. The compound exhibiting the highest agonist activity toward CB R (EC =7.53±3.15 nm) had a selectivity over CB R of more than 1328-fold. Moreover, structure-activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB R.