A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo.
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.
Alimentary Pharmabiotic Centre (APC) Microbiome Institute, University College Cork, Cork, Ireland.
Elena
E
Pastor-Cavada
Department of Chemistry and the Analytical and Biological Chemistry Research Facility (ABCRF), University College Cork, Cork, Ireland.
Leticia M
LM
Pardo
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Dalia
D
Kandil
Alimentary Pharmabiotic Centre (APC) Microbiome Institute, University College Cork, Cork, Ireland.
Cristina
C
Torres-Fuentes
Department of Chemistry and the Analytical and Biological Chemistry Research Facility (ABCRF), University College Cork, Cork, Ireland.
Sarah L
SL
Clarke
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Hamdy
H
Shaban
Department of Chemistry and the Analytical and Biological Chemistry Research Facility (ABCRF), University College Cork, Cork, Ireland.
Gerard P
GP
McGlacken
Alimentary Pharmabiotic Centre (APC) Microbiome Institute, University College Cork, Cork, Ireland.|Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Harriet
H
Schellekens
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D054440:Receptors, Ghrelin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D011728:Pyridones; D054440:Receptors, Ghrelin; D011993:Recombinant Fusion Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C017679:2-hydroxypyridine; D002118:Calcium