Photochromic peptidic NPY Y₄ receptor ligands

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Molecular Biology

Background:

• The neuropeptide Y (NPY) Y4 receptor (Y4R) is a G protein-coupled receptor targeted by pancreatic polypeptide.
• Selective Y4R agonists are investigated as potential therapeutics for obesity treatment.
• Dimeric peptidic Y4R agonists with flexible aliphatic linkers show high potency.

Purpose of the Study:

• To synthesize and characterize photoresponsive Y4R ligands with rigid photochromic linkers.
• To explore the structural requirements for Y4R binding using photochromic linkers.
• To assess the impact of linker rigidity on Y4R ligand affinity and activity.

Main Methods:

• Synthesis of dimeric peptidic ligands incorporating photochromic chromophores (azobenzene, azopyrazole, diethienylethene, fulgimide).
• Evaluation of Y4R binding affinity for synthesized ligands.
• Assessment of photoisomer-dependent differences in affinity and activity.

Main Results:

• Synthesized photoresponsive Y4R ligands with rigid photochromic linkers exhibited high Y4R affinity.
• Replacement of flexible aliphatic linkers with rigid photochromic linkers was well-tolerated for Y4R binding.
• Differences in affinity and activity between photoisomers were marginal, indicating linker flexibility is not critical.

Conclusions:

• Rigid photochromic linkers can be successfully incorporated into dimeric Y4R agonists without compromising binding affinity.
• The linking element's flexibility is less critical for achieving high-affinity binding to the Y4 receptor.
• These findings provide insights into the structural basis of Y4R ligand design for potential obesity therapeutics.