Medicinal chemistry, pharmacology, and therapeutic potential of α-conotoxins antagonizing the α9α10 nicotinic acetylcholine receptor

alpha-Conotoxins are disulfide-rich and well-structured peptides, most of which can block nicotinic acetylcholine receptors (nAChRs) with exquisite selectivity and potency. There are various nAChR subtypes, of which the alpha 9 alpha 10 nAChR functions as a heteromeric ionotropic receptor in the mammalian cochlea and mediates postsynaptic transmission from the medial olivocochlear. The alpha 9 alpha 10 nAChR subtype has also been proposed as a target for the treatment of neuropathic pain and the suppression of breast cancer cell proliferation. Therefore, alpha conotoxins targeting the alpha 9 alpha 10 nAChR are potentially useful in the development of specific therapeutic drugs and pharmacological tools. Despite dissimilarities in their amino acid sequence and structures, these conopeptides are potent antagonists of the alpha 9 alpha 10 nAChR subtype. Consequently, the activity and stability of these peptides have been subjected to chemical modifications. The resulting synthetic analogues have not only functioned as molecular probes to explore ligand binding sites of the alpha 9 alpha 10 nAChR, but also have the potential to become candidates for drug development. From the perspectives of medicinal chemistry and pharmacology, we highlight the structure and function of the alpha 9 alpha 10 nAChR and review studies of alpha-conotoxins targeting it, including their three-dimensional structures, structure optimization strategies, and binding modes at the alpha 9 alpha 10 nAChR, as well as their therapeutic potential. (c) 2020 Elsevier Inc. All rights reserved.