Mechanism of Action and Structure-Activity Relationship of a-Conotoxin Mr1.1 at the Human a9a10 Nicotinic Acetylcholine Receptor

alpha-Conotoxins (alpha-CTxs) can selectively target nicotinic acetylcholine receptors (nAChRs) and are important drug leads for the treatment of cancer, chronic pain, and neuralgia. Here, we chemically synthesized a formerly defined rat alpha 7 nAChR targeting alpha-CTx Mr1.1 and evaluated its activity at human nAChRs. Mr1.1 was most potent at the human (h) alpha 9 alpha 10 nAChR with a half-maximal inhibitory concentration (IC50) of 92.0 nM. Molecular dynamic simulations suggested that Mr1.1 favorably binds at the alpha 10(+)alpha 9(-) and alpha 9(+)alpha 9(-) sites via hydrogen bonds and salt bridges, stabilizing the channel in a closed conformation. Although Mr1.1 and another antagonist, alpha-CTx Vc1.1 share high sequence similarity and disulfide-bond framework, Mr1.1 has distinct orientations at h alpha 9 alpha 10. Based on the Mr1.1-h alpha 9 alpha 10 model, analogues were generated, and the more potent Mr1.1[S4Dap], antagonized h alpha 9 alpha 10 with an IC50 of 4.0 nM. Furthermore, Mr1.1[S4Dap] displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.

Automated summary

Alpha-conotoxins can target specific receptors to treat diseases such as cancer, chronic pain, and neuralgia. Researchers have synthesized a substance that can target a specific receptor in humans and found that it has strong activity and antagonistic effects, making it a promising drug candidate.