학술논문
GPR103 Antagonists DemonstratingAnorexigenic Activityin Vivo: Design and Development of Pyrrolo[2,3-c]pyridines That Mimic the C-Terminal Arg-Phe Motif of QRFP26.
Document Type
Article
Author
Georgsson, Jennie; Bergström, Fredrik; Nordqvist, Anneli; Watson, Martin J.; Blundell, Charles D.; Johansson, Magnus J.; Petersson, Annika U.; Yuan, Zhong-Qing; Zhou, Yiqun; Kristensson, Lisbeth; Kakol-Palm, Dorota; Tyrchan, Christian; Wellner, Eric; Bauer, Udo; Brodin, Peter; Svensson Henriksson, Anette
Source
Subject
*APPETITE depressants
*DRUG design
*PYRIDINE
*DRUG development
*G protein coupled receptors
*NEUROPEPTIDES
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Language
ISSN
0022-2623
Abstract
GPR103,a G-protein coupled receptor, has been reported to haveorexigenic properties through activation by the endogenous neuropeptideligands QRFP26 and QRFP43. Recognizing that central administrationof QRFP26 and QRFP43 increases high fat food intake in rats, we decidedto investigate if antagonists of GPR103 could play a role in managingfeeding behaviors. Here we present the development of a new seriesof pyrrolo[2,3-c]pyridines as GPR103 small moleculeantagonists with GPR103 affinity, drug metabolism and pharmacokineticsand safety parameters suitable for drug development. In a preclinicalobesity model measuring food intake, the anorexigenic effect of apyrrolo[2,3-c]pyridine GPR103 antagonist was demonstrated.In addition, the dynamic 3D solution structure of the C-terminal heptapeptideof the endogenous agonist QRFP26(20–26)was determinedusing NMR. The synthetic pyrrolo[2,3-c]pyridine antagonistswere compared to this experimental structure, which displayed a possibleoverlay of pharmacophore features supportive for further design ofGPR103 antagonists. [ABSTRACT FROM AUTHOR]