P2X3 Receptor Ligands: Structural Features and Potential Therapeutic Applications

Recommended tool compounds and drugs for blocking P2X and P2Y receptors

“…The orally administered potent and selective allosteric P2X3 antagonist gefapixant (AF-219, 11) successfully passed a phase III clinical trial for the treatment of refractory chronic cough [23] and is likely to become the first P2X3 receptor antagonist that will be approved as a drug [24]. This has revived the field, and more P2X3 receptor antagonists are now being developed and clinically evaluated for various indications (see, e.g., [21,[25][26][27]). The etymology of the international non-proprietary name (INN) "gefapixant" is explained in Fig.…”

“…In contrast, the imidazopyridine derivative BLU-5937 ( 14) was reported to be selective for the homomeric P2X3 receptor; it is currently evaluated in clinical trials for the treatment of chronic cough and pruritus [29]. Eliapixant (BAY-181780, 15), another potent and selective P2X3 receptor antagonist [21,27,30], has completed a phase 2a clinical trial for the treatment of refractory chronic cough [25] and is further clinically evaluated for the treatment of overactive bladder; another pursued indication is neuropathic pain. A further P2X3 antagonist with undisclosed structure (S-600918) is evaluated in clinical studies [10,31].…”

“…Antagonist AZ10606120 24 has a particularly high water solubility (25 mM), while compounds 26-28 have been described to penetrate well into the brain. JNJ47965567 (27) and related antagonists were co-crystallized with the human P2X7 receptor and shown to interact with a peripheral binding site far from the orthosteric ATP binding region (see Fig. 2) [43].…”

“…2). The crystal structures of the human P2X7 receptor with the antagonist JNJ47965567 (27) and four other antagonists identified a common allosteric drug binding site in a groove formed between two adjacent subunits in the upper body domain of the receptor [43]. The allosteric drug binding pocket becomes narrower upon ATP binding, a conformational rearrangement that is crucial for P2X7 receptor channel opening.…”

Current Clinical Options for the Management of Itch in Atopic Dermatitis

“…P2X3 is an ionotropic receptor that is expressed on the terminals of primary afferent sensory neurons of the dorsal root ganglia (DRG), spinal cord, and brain, mediating pain sensation. 93 BLU-5937, a P2X3 agonist, is currently under Phase II clinical evaluation for use in AD (NCT04693195, 2021).…”