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

J Med Chem. 2020 May 28;63(10):5274-5286. doi: 10.1021/acs.jmedchem.0c00027. Epub 2020 May 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Neuropeptides / chemistry*
  • Neuropeptides / metabolism*
  • Neuropeptides / pharmacology
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / metabolism*
  • Peptides, Cyclic / pharmacology
  • Protein Multimerization / drug effects
  • Protein Multimerization / physiology
  • Receptors, Neuropeptide Y / antagonists & inhibitors
  • Receptors, Neuropeptide Y / metabolism*

Substances

  • 1229U91
  • Neuropeptides
  • Peptides, Cyclic
  • Receptors, Neuropeptide Y
  • neuropeptide Y-Y1 receptor
  • neuropeptide Y4 receptor