Development of Conformationally Constrained α-RgIA Analogues as Stable Peptide Antagonists of Human α9α10 Nicotinic Acetylcholine Receptors

J Med Chem. 2020 Aug 13;63(15):8380-8387. doi: 10.1021/acs.jmedchem.0c00613. Epub 2020 Jul 16.


Non-opioid therapeutics for the treatment of neuropathic pain are urgently needed to address the ongoing opioid crisis. Peptides from cone snail venoms have served as invaluable molecules to target key pain-related receptors but can suffer from unfavorable physicochemical properties, which limit their therapeutic potential. In this work, we developed conformationally constrained α-RgIA analogues with high potency, receptor selectivity, and enhanced human serum stability to target the human α9α10 nicotinic acetylcholine receptor. The key lactam linkage introduced in α-RgIA fixed the favored globular conformation and suppressed disulfide scrambling. The NMR structure of the macrocyclic peptide overlays well with that of α-RgIA4, demonstrating that the cyclization does not perturb the overall conformation of backbone and key side-chain residues. Finally, a molecular docking model was used to rationalize the selective binding between a macrocyclic analogue and the α9α10 nicotinic acetylcholine receptor. These conformationally constrained antagonists are therefore promising candidates for antinociceptive therapeutic intervention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Conotoxins / chemistry*
  • Conotoxins / pharmacology*
  • Conus Snail / chemistry
  • Drug Design
  • Humans
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology
  • Molecular Conformation
  • Molecular Docking Simulation
  • Nicotinic Antagonists / chemistry*
  • Nicotinic Antagonists / pharmacology*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Protein Subunits / metabolism
  • Receptors, Nicotinic / metabolism*
  • Xenopus laevis


  • Conotoxins
  • Macrocyclic Compounds
  • Nicotinic Antagonists
  • Peptides, Cyclic
  • Protein Subunits
  • Receptors, Nicotinic
  • conotoxin alpha-RgIA, Conus regius