Synthesis & Structure-Activity Relationship Studies of Bicyclic Derivatives as P2X3 Receptor Antagonists

Abstract

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system. P2X3 receptor is an ATP-gated cation channel distributed in C- and Aδ- primary afferent neurons. Additionally, it is known to be involved in neuropathic pain transmission mechanisms. Therefore, the P2X3 receptor is considered as a target for the treatment of neuropathic pain, and various antagonists have been developed. In the previous research, a bicyclic core structure was discovered as a new hit compound for P2X3 antagonist through AI-based screening. Since the hit compound has two chiral centers, stereoisomer compounds were synthesized for each configuration. Also, various groups were introduced for several moiety. A total of 27 derivatives were synthesized, and the compounds were tested with in vitro calcium influx assay to confirm activities as P2X3 receptor antagonists. Structure optimization was conducted through a structure-activity relationship (SAR) study, and 18a and 18i showed the best activities with IC50 values of 350 nM and 57 nM, respectively. This study aims to suggest possibility of novel bicyclic derivatives as P2X3 antagonists and provide new insight for the treatment of neuropathic pain.