Transient receptor potential vanilloid 1 (TRPV1) antagonists can inhibit the transmission of nociceptive signals from the peripheral to the central nervous system (CNS), providing a new strategy for pain relief. In this work, in order to develop potent, CNS-penetrant, and orally available TRPV1 antagonists, three series of novel molecules based on the key pharmacophore structures of classic TRPV1 ligands SB-705498 and MDR-652 were designed and synthesized. Through systematic in vitro and in vivo bioassays, (S)–N-(3-isopropylphenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide (7q) was finally identified, which had enhanced TRPV1 antagonistic activity (IC₅₀ (capsaicin) = 2.66 nM), excellent CNS penetration (brain/plasma ratio = 1.66), favorable mode-selectivity, good bioavailability, and no side effects of hyperthermia. Molecular docking and dynamics studies indicated that the high binding affinity of compound 7q to TRPV1 was related to multiple interactions, which resulted in significant conformational changes of TRPV1. Overall, our findings have led to a potent, mode-selective, and CNS-penetrant TRPV1 antagonist as a valuable lead for development of novel TRPV1 antagonists.

瞬时受体电位香草醛 1 (TRPV1) 拮抗剂可以抑制伤害性信号从外周向中枢神经系统 (CNS) 的传递，为缓解疼痛提供了新的策略。在这项工作中，为了开发有效的、CNS 渗透性和口服可用的 TRPV1 拮抗剂，设计和合成了三个基于经典 TRPV1 配体 SB-705498 和 MDR-652 的关键药效​​团结构的新型分子。通过系统的体外和体内生物测定，最终鉴定出具有增强的TRPV1拮抗活性的( S ) -N- (3-异丙基苯基)-2-(5-苯基噻唑-2-基)吡咯烷-1-甲酰胺( 7q ) （集成电路₅₀(辣椒素) = 2.66 nM)，出色的中枢神经系统渗透（脑/血浆比 = 1.66），良好的模式选择性，良好的生物利用度，并且没有热疗的副作用。分子对接和动力学研究表明，化合物7q与TRPV1的高结合亲和力与多重相互作用有关，导致TRPV1构象发生显着变化。总体而言，我们的研究结果导致了一种有效的、模式选择性的和 CNS 渗透性 TRPV1 拮抗剂，作为开发新型 TRPV1 拮抗剂的重要线索。