Title:Ghrelin Receptor Ligands: Design and Synthesis of Pseudopeptides and Peptidomimetics
Volume: 7
Issue: 3
Author(s): Aline Moulin, Luc Brunel, Pascal Verdie, Laurent Gavara, Jean Martinez and Jean-Alain Fehrentz
Affiliation:
Keywords:
Ghrelin, growth hormone, obesity.
Abstract: Mainly synthesized in the stomach, ghrelin is a peptide hormone which stimulates growth hormone secretion
and appetite, thus promoting food intake and body-weight gain. Historically, researchers started to work on the discovery
of ghrelin receptor ligands several years before the discovery of the ghrelin receptor and the hormone itself. Indeed peptides
able to stimulate growth hormone secretion (growth hormone releasing peptides, GHRPs) were found while the
mechanism of action and the target receptor were still unknown. Non peptidic agonists were then described (growth hormone
secretagogues, GHSs) and the receptor (GHS-R1a) identified in 1996. Three years later, the natural ligand of this
receptor (ghrelin) was isolated from stomach and its chemical synthesis allowed to show the physiological role of ghrelin
in energy balance. In this review, we present some pseudopeptide and peptidomimetic approaches used by researchers for
the design of ghrelin receptor ligands. We will start by the pioneering work of Bowers et al. on enkephalin analogues,
which was the starting point for the development of an impressive number of compounds, by several of the major worldwide
pharma companies. We will also describe the work achieved starting from a substance P derivative, which was one
of the first peptides identified as an antagonist of the newly discovered ghrelin receptor. Then we will review the structure
activity relationship study starting from the peptide ghrelin, which started with the discovery of this peptide in 1999. We
will also focus on a more recent work based on macrocyclic peptidic analogues for the development of ghrelin receptor
ligands.
