Heterodimeric Analogues of the Potent Y1R Antagonist 1229U91, Lacking One of the Pharmacophoric C-Terminal Structures, Retain Potent Y1R Affinity and Show Improved Selectivity over Y4R

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

Abstract

The cyclic dimeric peptide 1229U91 (GR231118) has an unusual structure and displays potent, insurmountable antagonism of the Y1 receptor. To probe the structural basis for this activity, we have prepared ring size variants and heterodimeric compounds, identifying the specific residues underpinning the mechanism of 1229U91 binding. The homodimeric structure was shown to be dispensible, with analogues lacking key pharmacophoric residues in one dimer arm retaining high antagonist affinity. Compounds 11d-h also showed enhanced Y1R selectivity over Y4R compared to 1229U91.

Citation

Richardson, R. R., Richardson, R., Groenen, M., Liu, M., Mountford, S. J., Briddon, S. J., …Thompson, P. E. (2020). Heterodimeric Analogues of the Potent Y1R Antagonist 1229U91, Lacking One of the Pharmacophoric C-Terminal Structures, Retain Potent Y1R Affinity and Show Improved Selectivity over Y4R. Journal of Medicinal Chemistry, 63(10), 5274-5286. https://doi.org/10.1021/acs.jmedchem.0c00027

• Journal Article Type: Article
• Acceptance Date: Apr 30, 2020
• Online Publication Date: May 4, 2020
• Publication Date: May 28, 2020
• Deposit Date: May 11, 2020
• Publicly Available Date: May 5, 2021
• Journal: Journal of medicinal chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 63
• Issue: 10
• Pages: 5274-5286
• DOI: https://doi.org/10.1021/acs.jmedchem.0c00027
• Keywords: Molecular Medicine; Drug Discovery
• Public URL: https://nottingham-repository.worktribe.com/output/4417019
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00027
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in 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 https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00027