Decades of ghrelin receptor drug development have produced numerous peptide agonists for cachexia and growth hormone release, but the field is now shifting toward antagonists and inverse agonists for obesity treatment.
1 approval in decades of developmentDespite numerous clinical trials, only GHRP-2 was approved — for diagnostic use in Japan — highlighting the challenges of ghrelin receptor drug development
What the researchers found
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.
Why it matters
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.
How the study worked
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.
What this study cannot tell us
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.
How to read the evidence
This is a narrative review summarizing the clinical trial history of ghrelin receptor ligands. It provides a comprehensive overview but does not include systematic methodology or new experimental data.
When this study was published
Published in 2016, this review captures the field as it was pivoting toward antagonists. Significant developments in metabolic drug therapy (particularly GLP-1 agonists) have since transformed the obesity treatment landscape and may influence future ghrelin-targeted approaches.
The bigger picture
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.
Questions still open
- Could ghrelin receptor antagonists be combined with GLP-1 agonists for synergistic anti-obesity effects?
- Why have ghrelin receptor agonists largely failed in clinical trials despite strong preclinical data?
- Has the development of ghrelin receptor antagonists progressed further since this 2016 review?
Common questions
What is ghrelin and why target its receptor?
Why have ghrelin receptor drugs mostly failed despite strong science?
Read the original research
Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists.
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 48(1), 1-15
Citation
Vodnik, M; Štrukelj, B; Lunder, M. (2016). Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists.. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 48(1), 1-15. https://doi.org/10.1055/s-0035-1564149