New Compounds Block the Hunger Hormone Receptor to Fight Obesity and Diabetes

What the researchers found

The ghrelin receptor (GHSR) has unusually high constitutive activity, meaning it sends hunger and metabolic signals even when ghrelin is not present. An inverse agonist does not just block the receptor; it actively reduces this baseline signaling.

The researchers developed a series of compounds based on the 1,2,4-triazole chemical scaffold. By varying substituents at positions 3, 4, and 5, they created highly potent and selective GHSR inverse agonists. These compounds stabilize a specific inactive conformation of the receptor, effectively silencing its constant output.

In living systems, one of the most promising compounds affected insulin secretion in isolated rat pancreatic islets and counteracted ghrelin's appetite-stimulating effects in mice. This demonstrates both metabolic and appetite-related activity in vivo.

Why it matters

Ghrelin is called the hunger hormone. Its receptor (GHSR) is a compelling target for obesity and diabetes, but previous attempts to block it have struggled. Inverse agonists are more powerful than simple blockers because they silence the receptor's constant baseline activity. Small molecules (non-peptides) are easier to develop into pills than peptide-based drugs.

The numbers in context

Triazole scaffold; positions 3,4,5 varied; lead compound active on insulin and appetite in animals

How the study worked

Medicinal chemistry study with in vitro and in vivo testing. Researchers synthesized a library of triazole-based compounds, tested them for GHSR binding affinity and inverse agonist activity using cell-based assays measuring G protein activation. The most promising compounds were tested for effects on insulin secretion in rat pancreatic islets (ex vivo) and on feeding behavior in mice (in vivo).

Who was studied

Cell-based assays, rat pancreatic islets, mice (feeding behavior)

What this study cannot tell us

Animal testing was limited (rat islets and mouse feeding). No human safety or efficacy data. The triazole compounds' pharmacokinetics (absorption, distribution, metabolism) were not fully characterized. Long-term effects of suppressing GHSR constitutive activity are unknown and could have unintended consequences on growth hormone and glucose regulation.

How to read the evidence

Preliminary evidence. Animal studies showed effects on appetite and insulin, but no human safety or efficacy data exists.

When this study was published

Published in 2020. Ghrelin receptor pharmacology continues to be explored for obesity and metabolic disease.

The bigger picture

Ghrelin receptor drugs have been difficult to develop because the receptor has unusually high constitutive activity. Inverse agonists address this by reducing baseline signaling, not just blocking ghrelin binding. This could lead to more effective anti-obesity drugs.

Questions still open

• What are the long-term safety profiles of chronic ghrelin receptor inverse agonism?
• Will these compounds work in obese humans where ghrelin signaling may be altered?
• Could inverse agonists be combined with GLP-1 drugs for enhanced weight loss?

Common questions

Read the original research

Development of Nonpeptidic Inverse Agonists of the Ghrelin Receptor (GHSR) Based on the 1,2,4-Triazole Scaffold.

Journal of medicinal chemistry, 63(19), 10796-10815

Citation

Haj Salah, Khoubaib Ben; Maingot, Mathieu; Blayo, Anne-Laure; M'Kadmi, Céline; Damian, Marjorie; Mary, Sophie; Cantel, Sonia; Neasta, Jérémie; Oiry, Catherine; Péraldi-Roux, Sylvie; Fernandez, Gimena; Romero, Guadalupe García; Perello, Mario; Marie, Jacky; Banères, Jean-Louis; Fehrentz, Jean-Alain; Denoyelle, Séverine. (2020). Development of Nonpeptidic Inverse Agonists of the Ghrelin Receptor (GHSR) Based on the 1,2,4-Triazole Scaffold.. Journal of medicinal chemistry, 63(19), 10796-10815. https://doi.org/10.1021/acs.jmedchem.9b02122