A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo.

Elena Pastor-Cavada,Hamdy Shaban,Dalia Kandil,Sarah L Clarke,Gerard P Mcglacken,Harriet Schellekens,Leticia M Pardo,Cristina Torres-Fuentes

doi:10.1038/srep36456

Elena Pastor-Cavada, Hamdy Shaban + Show 6 more

Open Access

https://doi.org/10.1038/srep36456

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Abstract

Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. In vivo tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand.

Highlights

Cachexia is a metabolic disorder or wasting syndrome, characterised by loss of weight, muscle atrophy, fatigue, weakness and significant loss of appetite, that affects millions of people worldwide, including as many as 80% of people with advanced cancer[1]
Ghrelin acts as an endogenous ligand for the growth hormone secretagogue receptor, or ghrelin receptor (GHS-R1a) and has a plethora of central and peripheral actions including the release of growth hormone from the pituitary gland[9,10,11,12,13,14]
Non-peptide mimetics of ghrelin are ideally poised for the development of successful, orally available administration, given the often inhibitory degradation of peptidic based structures[19], yet reports of non-peptidic GHS-R1a receptor agonists are rare

Summary

Introduction

Cachexia is a metabolic disorder or wasting syndrome, characterised by loss of weight, muscle atrophy, fatigue, weakness and significant loss of appetite, that affects millions of people worldwide, including as many as 80% of people with advanced cancer[1]. In our set of studies, pyridone 8 was directly compared to the endogenous GHS-R1a receptor agonist, ghrelin and the non-peptide agonist, MK-0677, in the calcium mobilisation assay using Hek-GHS-R1a-EGFP cells (for details, see SI, Figure S2).

Results

Conclusion