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

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.