Ghrelin Receptor Drug Development: From Peptide Agonists to Obesity-Targeting Antagonists

The ghrelin receptor (GHS-R1a) ligand field has evolved from peptide growth hormone secretagogues derived from Met-enkephalin to a diverse landscape of peptides, peptidomimetics, and small molecules. Several agonists reached clinical trials for growth hormone release, gastric emptying, and cachexia, but only GHRP-2 achieved approval (diagnostic use in Japan). The field has pivoted toward antagonists and inverse agonists targeting obesity and overweight, though none had reached market at the time of review.

Narrative review surveying the development history of ghrelin receptor ligands, including peptides, peptidomimetics, and small molecules. Focuses on compounds that reached clinical trials, covering agonists, antagonists, and inverse agonists with analysis of their therapeutic potential.

The ghrelin system sits at the crossroads of hunger, metabolism, and growth hormone regulation. Despite the clinical failures of agonists, the ghrelin receptor remains a compelling drug target — particularly for obesity, where blocking hunger signaling could complement GLP-1-based approaches. Understanding past failures is essential for developing the next generation of anti-obesity peptide drugs.

The ghrelin receptor story is a cautionary tale in peptide drug development — a scientifically compelling target where most candidates failed in clinical trials. However, with the obesity epidemic driving unprecedented investment in metabolic drugs (including GLP-1 agonists), ghrelin antagonists may find renewed interest as part of combination approaches to weight management.

This is a 2016 review and does not include developments from the past decade. The review summarizes existing literature without generating new data. Many of the compounds discussed never progressed beyond early clinical trials, and the reasons for clinical failure are not always clear from the available data.