Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.
The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.
Overton
Hilary A
HA
(OSI)Prosidion, Windrush Court, Watlington Road, Oxford OX4 6LT, UK. hoverton@prosidion.com
Babbs
Adam J
AJ
Doel
Sheila M
SM
Fyfe
Matthew C T
MC
Gardner
Lisa S
LS
Griffin
Graeme
G
Jackson
Helen C
HC
Procter
Martin J
MJ
Rasamison
Chrystelle M
CM
Tang-Christensen
Mads
M
Widdowson
Peter S
PS
Williams
Geoffery M
GM
Reynet
Christine
C
D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004032:Diet; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005247:Feeding Behavior / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000188:drug therapy; D009829:Oleic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D013997:Time Factors; D015003:Yeasts / Q000378:metabolism
D001067:Appetite Depressants; D063388:Endocannabinoids; D009829:Oleic Acids; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C488250:oleoylethanolamide; D000242:Cyclic AMP