Mechanism of Action and Structure-Activity Relationship of α-Conotoxin Mr1.1 at the Human α9α10 Nicotinic Acetylcholine Receptor
Publication Name
Journal of Medicinal Chemistry
Abstract
α-Conotoxins (α-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 α7 nAChR targeting α-CTx Mr1.1 and evaluated its activity at human nAChRs. Mr1.1 was most potent at the human (h) α9α10 nAChR with a half-maximal inhibitory concentration (IC50) of 92.0 nM. Molecular dynamic simulations suggested that Mr1.1 favorably binds at the α10(+)α9(-) and α9(+)α9(-) sites via hydrogen bonds and salt bridges, stabilizing the channel in a closed conformation. Although Mr1.1 and another antagonist, α-CTx Vc1.1 share high sequence similarity and disulfide-bond framework, Mr1.1 has distinct orientations at hα9α10. Based on the Mr1.1-hα9α10 model, analogues were generated, and the more potent Mr1.1[S4Dap], antagonized hα9α10 with an IC50of 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.
Open Access Status
This publication is not available as open access
Volume
65
Issue
24
First Page
16204
Last Page
16217
Funding Number
DP150103990
Funding Sponsor
Australian Research Council