The positive allosteric modulator C1 enhances Y4 receptor G-protein signaling and ligand binding while showing high selectivity for Y4 receptor over related subtypes.
The novel positive allosteric modulator C1 selectively enhances Y4R signaling and helps identify key structural domains and residues required for stabilizing the active ligand-bound conformation of the receptor.
Abstract The neuropeptide Y 4 receptor (Y 4 R) and its endogenous ligand pancreatic polypeptide (PP) are primarily involved in the regulation of satiety and energy balance and present relevant pharmacological targets. We characterized the novel Y 4 R positive allosteric modulator C1 that enhances Y 4 R G-protein signaling, ligand binding, and arrestin-3 recruitment to Y 4 R. Comparison with a close analog revealed the structural importance of an ethyl acetate moiety for Y 4 R affinity and PAM activity at the G-protein pathway. C1 shows a high selectivity for the Y 4 R, while signaling of the related subtypes Y 1 R, Y 2 R, and Y 5 R is not affected. Y 4 R G-protein signaling is even potentiated by the low-affinity agonists neuropeptide Y and peptide YY. Binding affinity of the endogenous ligands to Y 4 R is enhanced by C1, indicating a stabilization of the ligand-bound Y 4 R conformation. Using Y 4 R/Y 1 R chimera, important Y 4 R domains for C1 activity were identified. Single point mutagenesis and computational docking pinpointed hot-spot residues at Y 4 R important for stabilizing the active ligand-bound conformation.
Schüß et al. (2026) studied this question. The positive allosteric modulator C1 enhances Y4 receptor G-protein signaling and ligand binding while showing high selectivity for Y4 receptor over related subtypes.