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.

doi:10.1021/acs.jmedchem.0c00027

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.

Authors

Rachel R. Richardson

Rachel Richardson

Marleen Groenen

Mengjie Liu

Simon J. Mountford

Dr STEPHEN BRIDDON stephen.briddon@nottingham.ac.uk
PRINCIPAL RESEARCH FELLOW

Dr Nick Holliday nicholas.holliday@nottingham.ac.uk
ASSOCIATE PROFESSOR

Philip E. Thompson

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., Holliday, N. D., & 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