Optically pure, structural and fluorescent analogues of a dimeric Y4 receptor agonist derived by an olefin metathesis approach

Liu, Mengjie; Mountford, Simon J.; Richardson, Rachel R.; Groenen, Marleen; Holliday, Nicholas D.; Thompson, Philip E.

Abstract

The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective Neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors, and as a lead compound for anti-obesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labelled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)- diaminosuberoyl containing peptide, (R,R)-1 had markedly higher affinity and agonist efficacy than its (S,S)-counterpart. Furthermore the sulfo-Cy5 labelled (R,R)-14 retained high agonist potency as a novel fluorescent ligand for imaging Y4 receptors.

Citation

Liu, M., Mountford, S. J., Richardson, R. R., Groenen, M., Holliday, N. D., & Thompson, P. E. (2016). Optically pure, structural and fluorescent analogues of a dimeric Y4 receptor agonist derived by an olefin metathesis approach. Journal of Medicinal Chemistry, 59(13), 6059-6069. https://doi.org/10.1021/acs.jmedchem.6b00310

• Journal Article Type: Article
• Acceptance Date: Jun 13, 2016
• Online Publication Date: Jun 28, 2016
• Publication Date: Jul 14, 2016
• Deposit Date: Jun 17, 2016
• Publicly Available Date: Jun 28, 2016
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 59
• Issue: 13
• Pages: 6059-6069
• DOI: https://doi.org/10.1021/acs.jmedchem.6b00310
• Public URL: https://nottingham-repository.worktribe.com/output/795390
• Publisher URL: http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00310
• Contract Date: Jun 17, 2016