Figure 3.

Small scaffolds for P2R antagonists, including PAMs and NAMs related to pyridoxal phosphate (A), N,N′-diarylureas that allosterically antagonize P2Y₁R (B) and various P2X3R, P2X7R and P2Y₁₂R (C) antagonists. Gefapixant, BLU-5937, AZD9056, CE-224,535, GSK1482160 and JNJ-54175446 have been in clinical trials [66–68,116–120]. The pyridoxal phosphates are known to interact with various P2X and P2Y receptors as antagonists or PAMs, while the diarylureas are specific for P2Y₁R. This specificity is a function of their unusual binding site on the outer surface of the receptor where the urea forms a bidentate H-bond with a backbone carbonyl group. Affinities of many these compounds and their original references are collected [6, 66–68,116–120]. Years shown for each compound indicate an early, major report in the literature.