Design, Synthesis, and Pharmacological Activities of Dynorphin A Analogs Cyclized by Ring-Closing Metathesis
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Issue Date
2009-09-24Author
Fang, Wei-Jie
Gui, Yanjun
Murray, Thomas F.
Aldrich, Jane V.
Publisher
American Chemical Society
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm900577k.
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Show full item recordAbstract
Dynorphin A (Dyn A) is an endogenous ligand for kappa (κ) opioid receptors. To restrict the conformational mobility, we synthesized several cyclic Dyn A-(1-11)NH2 analogs on solid phase utilizing ring-closing metathesis (RCM) between the side chains of allylglycine (AllGly) residues incorporated in positions 2, 5 and/or 8. Cyclizations between the side chains of AllGly gave reasonable yields (56–74%) of all of the desired cyclic peptides. Both the cis and trans isomers were obtained for all of the cyclic peptides, with the ratio of cis to trans isomers depending on the position and stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH2 analogs examined exhibit low nanomolar binding affinity for κ opioid receptors (Ki = 0.84–11 nM). In two of the three cases the configuration of the double bond has a significant influence on the opioid receptor affinity and agonist potency. All of the peptides inhibited adenylyl cyclase (AC) activity in a concentration-dependent manner with full or close to full agonist activity. These potent Dyn A analogs are the first ones cyclized by RCM.
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Citation
Fang, W.-J., Cui, Y., Murray, T. F., & Aldrich, J. V. (2009). Design, Synthesis, and Pharmacological Activities of Dynorphin A Analogs Cyclized by Ring-Closing Metathesis. Journal of Medicinal Chemistry, 52(18), 5619–5625. http://doi.org/10.1021/jm900577k
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