C-Terminal modifications of apelin-13 significantly change ligand binding, receptor signaling, and hypotensive action

J Med Chem. 2015 Mar 12;58(5):2431-40. doi: 10.1021/jm501916k. Epub 2015 Feb 24.


Apelin is the endogenous ligand of the APJ receptor, a member of the G protein-coupled receptor family. This system plays an important role in the regulation of blood pressure and cardiovascular functions. To better understand the role of its C-terminal Phe(13) residue on ligand binding, receptor signaling, and hypotension, we report a series of modified analogues in which Phe(13) was substituted by unnatural amino acids. These modifications delivered new compounds exhibiting higher affinity and potency to inhibit cAMP accumulation compared to apelin-13. In particular, analogues Bpa(13) or (α-Me)Phe(13) were 30-fold more potent to inhibit cAMP accumulation than apelin-13. Tyr(OBn)(13) substitution led to a 60-fold improvement in binding affinity and induced stronger and more sustained drop in blood pressure compared to apelin-13. Our study identified new potent analogues of apelin-13, which represent valuable probes to better understand its structure-function relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Apelin
  • Blood Pressure / drug effects*
  • Cyclic AMP / metabolism*
  • Hypotension / drug therapy*
  • Intercellular Signaling Peptides and Proteins / chemistry*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • Ligands
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction
  • Structure-Activity Relationship


  • Apelin
  • Apln protein, rat
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Receptors, G-Protein-Coupled
  • apelin-13 peptide
  • Cyclic AMP