Conformational Constraint between Aromatic Residue Side Chains in the “Message” Sequence of the Peptide Arodyn Using Ring Closing Metathesis Results in a Potent and Selective Kappa Opioid Receptor Antagonist
- Solomon A. GisembaSolomon A. GisembaDepartment of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United StatesDepartment of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United StatesMore by Solomon A. Gisemba
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- Michael J. FerracaneMichael J. FerracaneDepartment of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United StatesDepartment of Chemistry, University of Redlands, Redlands, California 92373, United StatesMore by Michael J. Ferracane
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- Thomas F. MurrayThomas F. MurrayDepartments of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, Nebraska 68102, United StatesMore by Thomas F. Murray
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- Jane V. Aldrich*Jane V. Aldrich*Email: [email protected]Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United StatesDepartment of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United StatesMore by Jane V. Aldrich
Abstract
Kappa opioid receptor (KOR) antagonists have recently shown potential for treating drug addiction and mood disorders. The linear acetylated dynorphin A analog arodyn (Ac[Phe1,2,3,Arg4,d-Ala8]dynorphin A-(1–11)NH2), synthesized in our laboratory, demonstrated potent and selective KOR antagonism. Cyclization of arodyn could potentially stabilize the bioactive conformation and enhance its metabolic stability. The cyclization strategy employed involved ring closing metathesis between adjacent meta- or para-substituted Tyr(allyl) residues in the “message” sequence that were predicted in a docking study to yield analogs that would bind to the KOR with binding poses similar to arodyn. Consistent with the modeling, the resulting analogs retained KOR affinity similar to arodyn; the peptides involving cyclization between para O-allyl groups also retained high KOR selectivity, with one analog exhibiting KOR antagonist potency (KB = 15 nM) similar to arodyn. These promising cyclized analogs with constrained aromatic residues represent novel leads for further exploration of KOR pharmacology.
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This article is cited by 3 publications.
- Rama Ballouze, Salizawati Muhamad Salhimi, Noratiqah Mohtar, Siti Sarah Fazalul Rahiman. Dynorphin 1-17 biotransformation peptides: properties, challenges and solutions for future therapeutics development. Future Medicinal Chemistry 2023, 15
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, 791-808. https://doi.org/10.4155/fmc-2023-0016
- Wei-Jie Fang, Thomas F. Murray, Jane V. Aldrich. Analogs of the κ opioid receptor antagonist arodyn cyclized by ring-closing metathesis retain κ opioid receptor affinity, selectivity and κ opioid receptor antagonism. Medicinal Chemistry Research 2021, 30
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, 1397-1407. https://doi.org/10.1007/s00044-021-02758-x
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, M1215. https://doi.org/10.3390/M1215