Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB2 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 CB2 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 CB2 R in calcium mobilization assays, and four displayed CB2 R agonist activity, with EC50 values below 30 nm. The compound exhibiting the highest agonist activity toward CB2 R (EC50 =7.53±3.15 nm) had a selectivity over CB1 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 CB2 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 CB2 R.
['Qian|Hai-Yan|HY|', 'Wang|Zhi-Long|ZL|', 'Chen|Li-Li|LL|', 'Pan|You-Lu|YL|', 'Xie|Xiao-Yu|XY|', 'Xie|Xin|X|', 'Chen|Jian-Zhong|JZ|0000-0001-7990-7876']
D000818:Animals D001665:Binding Sites D016466:CHO Cells D063386:Cannabinoid Receptor Agonists D003412:Cricetulus D015195:Drug Design D008024:Ligands D062105:Molecular Docking Simulation D015394:Molecular Structure D011743:Pyrimidines D043884:Receptor, Cannabinoid, CB1 D043885:Receptor, Cannabinoid, CB2 D013329:Structure-Activity Relationship D014227:Triazines
ligands CB1R CB2R cannabinoids heteroaryl pyrimidines heteroaryl triazines