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Alpha-Conotoxins (α-CTxs) are short disulfide-rich peptides isolated from the venom of the predatory marine snails of the genus Conus,which are competitive antagonists of different subtypes of nicotinic acetylcholine receptors (nAChRs).nAChRs are cationic channels that mediate fast synaptic transmission within the peripheral and central nervous system and present important targets for the development of novel drugs for the treatment of pain and various disorders of the central nervous system.α-CTx TxIA is a 16-residue conotoxin with 4/7 intercysteine spacing and was found by Dutertre et al firstly,which was also isolated from Conus textile native to the South China Sea in our lab.α-CTx TxIA had been characterized on oocyte-expressed nAChRs and shown to be selective primarily for the α3β2 nAChR subtype.In the present study,we synthesized three isomers of α-CTx TxIA with selective oxidation strategy and examined the structures and activities of the globular isomer and the non-native isomers.The "globular" isomer with native peptide disulfide bond connectivity was the most potent on α3β2 nAChRs expressed in Xenopus oocytes,which had an IC50 of 3-9.5 nM and was similar with the IC50 reported for the native toxin (2 nM).The ribbon isomer of α-CTx TxIA was 10 times less potent than the globular isomer.While beads isomer showed no inhibition on α3β2 nAChRs.