Mahmood Abid, Munir Rubina, Zia-Ur-Rehman Muhammad, Javid Noman, Shah Syed Jawad Ali, Noreen Lubna, Sindhu Tayyaba Allamgir, Iqbal Jamshed
Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.
Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan.
ACS Omega. 2021 Sep 16;6(38):25062-25075. doi: 10.1021/acsomega.1c04302. eCollection 2021 Sep 28.
P2X receptors have the ability to regulate various physiological functions like neurotransmission, inflammatory responses, and pain sensation. Such physiological properties make these receptors a new target for the treatment of pain and inflammation. Several antagonists of P2X receptors have been studied for the treatment of neuropathic pain and neurodegenerative disorders but potency and selectivity are the major issues with these known inhibitors. Sulfonamide derivatives were reported to be potent inhibitors of P2X receptors. In this study, sulfonamide carrying precursor hydrazide was synthesized by a facile method that was subsequently condensed with methyl (hetero)arylketones to obtain a series of new (hetero)aryl ethylidenes. These compounds were screened for inhibitory potential against -P2X2, -P2X4, -P2X5, and -P2X7 receptors to find their potency and selectivity. Computational studies were performed to confirm the mode of inhibition as well as type of interaction between ligand and target site. In calcium signaling experiments, compound was found to be the most potent and selective inhibitor of -P2X2 and -P2X7 receptors with IC ± standard error of the mean (SEM) values of 0.32 ± 0.01 and 1.10 ± 0.21 μM, respectively. Compounds and exhibited selective inhibition for -P2X7 receptor, whereas , , and expressed selective inhibitions toward -P2X2 receptor that were comparable to the positive control suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS).
P2X受体具有调节多种生理功能的能力，如神经传递、炎症反应和痛觉。这些生理特性使这些受体成为治疗疼痛和炎症的新靶点。已经对几种P2X受体拮抗剂进行了治疗神经性疼痛和神经退行性疾病的研究，但效力和选择性是这些已知抑制剂的主要问题。据报道，磺胺衍生物是P2X受体的有效抑制剂。在本研究中，通过简便方法合成了携带前体酰肼的磺胺，随后将其与甲基（杂）芳基酮缩合，以获得一系列新的（杂）芳基亚乙基。对这些化合物针对P2X2、P2X4、P2X5和P2X7受体的抑制潜力进行了筛选，以确定它们的效力和选择性。进行了计算研究，以确认抑制模式以及配体与靶位点之间的相互作用类型。在钙信号实验中，发现化合物是P2X2和P2X7受体最有效和选择性的抑制剂，其IC50±平均标准误差（SEM）值分别为0.32±0.01和1.10±0.21μM。化合物和对P2X7受体表现出选择性抑制，而、和对P2X2受体表现出选择性抑制，其效果与阳性对照苏拉明和磷酸吡哆醛-6-偶氮苯基-2'，4'-二磺酸（PPADS）相当。
