TY - JOUR
T1 - 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
AU - Richardson, Rachel R.
AU - Groenen, Marleen
AU - Liu, Mengjie
AU - Mountford, Simon J.
AU - Briddon, Stephen J.
AU - Holliday, Nicholas D.
AU - Thompson, Philip E.
PY - 2020/5/28
Y1 - 2020/5/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085586065&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.0c00027
DO - 10.1021/acs.jmedchem.0c00027
M3 - Article
C2 - 32364733
AN - SCOPUS:85085586065
SN - 0022-2623
VL - 63
SP - 5274
EP - 5286
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 10
ER -