Therefore, P2X4 receptor antagonists might have potentials for the treatment of neuropathic pain,23 epilepsy, stroke, multiple sclerosis, and neurodegenerative diseases such as PD and AD.159,169 Paroxetine, a selective serotonin reuptake inhibitor, has shown to behave as an allosteric antagonist of P2X4Rs at high concentrations (IC50 = 2.45 μM, rat, and IC50 = 1.87 μM, human).170 Thus far, attempts to identify potent and selective antagonist of P2X4Rs have resulted in the discovery of allosteric ligands with low potency and poor aqueous solubility. Among these antagonists is the benzodiazepine derivative 5-BDBD (IC50 = 0.5 μM)171 and its analogs172 that possessed allosteric antagonism, but low potency at P2X4R.172 The urea derivative BX-430 was another allosteric P2X4 receptor antagonist with low potency (IC50 = 0.54 μM).173 An additional allosteric P2X4Rs antagonist is the high lipophilic and poor soluble carbamate PSB-12054 with good selectivity and reasonable potency at human P2X4Rs but much less potency at rat and mice P2X4Rs.174 An analog of PSB-12054, PSB-12062 with better solubility, was developed later and showed equal potency at human, rat, and mouse and good selectivity for P2X4R versus
