The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated in vitro. The acute glucose lowering effect was studied in lean wild-type and GPR120 null mice following oral or intravenous glucose tolerance tests. In vitro, in GPR120 overexpressing cells, both agonists signaled through Gαq, Gαs and the β-arrestin pathway. However, in mouse islets the signaling pathway was different since the agonists reduced cAMP production. The GPR120 agonists stimulated GLP-1 secretion both in vitro in STC-1 cells and in vivo following oral administration. In vivo GPR120 activation induced significant glucose lowering and increased insulin secretion after intravenous glucose administration in lean mice, while the agonists had no effect in GPR120 null mice. Exendin 9–39, a GLP-1 receptor antagonist, abolished the GPR120 induced effects on glucose and insulin following an intravenous glucose challenge. In conclusion, GLP-1 secretion is an important mechanism behind the acute glucose lowering effect following specific GPR120 activation.

GPR103, a G-protein coupled receptor, has been reported to have orexigenic properties through activation by the endogenous neuropeptide ligands QRFP26 and QRFP43. Recognizing that central administration of QRFP26 and QRFP43 increases high fat food intake in rats, we decided to investigate if antagonists of GPR103 could play a role in managing feeding behaviors. Here we present the development of a new series of pyrrolo[2,3-c]pyridines as GPR103 small molecule antagonists with GPR103 affinity, drug metabolism and pharmacokinetics and safety parameters suitable for drug development. In a preclinical obesity model measuring food intake, the anorexigenic effect of a pyrrolo[2,3-c]pyridine GPR103 antagonist was demonstrated. In addition, the dynamic 3D solution structure of the C-terminal heptapeptide of the endogenous agonist QRFP26(20-26) was determined using NMR. The synthetic pyrrolo[2,3-c]pyridine antagonists were compared to this experimental structure, which displayed a possible overlay of pharmacophore features supportive for further design of GPR103 antagonists.

Preclinical data indicate that GPR103 receptor and its endogenous neuropeptides QRFP26 and QRFP43 are involved in appetite regulation. A high throughput screening (HTS) for small molecule GPR103 antagonists was performed with the clinical goal to target weight management by modulation of appetite. A high hit rate from the HTS and initial low confirmation with respect to functional versus affinity data challenged us to revise the established screening cascade. To secure high quality data while increasing throughput, the binding assay was optimized on quality to run at single concentration. This strategy enabled evaluation of a larger fraction of chemical clusters and singletons delivering 17 new compound classes for GPR103 antagonism. Representative compounds from three clusters are presented. One of the identified clusters was further investigated, and an initial structure−activity relationship study is reported. The most potent compound identified had a pIC 50 of 7.9 with an improved ligand lipophilic efficiency. KEYWORDS: G-protein coupled receptor, high throughput screening, appetite regulation, SP9155, 26RFa, 43RFa, GPCR O besity is a global epidemic associated with increased morbidity and mortality.1,2 GPR103 is a family A Gprotein coupled receptor first described in 2001.3 The endogenous GPR103 neuropeptide ligands QRFP26 and the N-terminal elongated QRFP43 were discovered by three different groups 4−6 and paired with an, at that time, orphan receptor GPR103.4,5 QRFP26 and QRFP43 are RFamide peptides encompassing the C-terminal Arg-Phe-NH 2 motif common to all RFamide family members. Structure−activity relationships (SAR) studies of QRFP26 show that the terminal Phe 24 -Arg 25 -Phe 26 motif 7 and the C-terminal amidation common to the RFamide family are very important for functional activity. 5,7 Gene expression data show that GPR103 and its endogenous GPR103 neuropeptide ligands are expressed in ventromedial nuclei, lateral hypothalamus, and arcuate nucleus, which are areas known to be involved in the control of feeding behavior and body weight. 4,5,8−10 Peripherally GPR103 is found to be expressed in heart, kidney, retina, and testis but at considerably lower levels. 4 Preclinical data demonstrate that intracerebroventricular injections (i.c.v.) of the endogenous agonists QRFP26 and QRFP43, 6,10,11 as well as synthetic peptidomimetic agonists 12 increase feeding in rodents. Also, prepro-QRFP26 mRNA is up-regulated in the hypothalamus in fasted mice as well as in ob/ob and in db/db mice compared to fed mice and wild-type mice.10 High-fat feeding of rats also results in increased expression of endogenous ligands but does not alter GPR103 expression. Data taken together points at GPR103 to have a function in controlling appetite, suggesting that inhibition of the orexigenic effect from QRFP26/QRFP43 receptor activation would promote reduced body weight by modulation of appetite.Antagonists of GPR103 in context of weight management have previously been published in four different patents covering ...

Compound 25a column 3 should be 4-CH 3 instead of 3-CH 3 .Compound 25c column 3 should be 3-CH 3 instead of 4-CH 3 .Compound 25e column 3 should be (+)-4-CH 3 instead of (+)-7-CH 3 .Compound 25f column 3 should be (−)-4-CH 3 instead of (−)-7-CH 3 .

Relaxin family peptide receptor 3 (RXFP3) is a G-protein coupled receptor mainly expressed in the brain and involved in appetite regulation. Previous studies in lean Wistar rats during the light phase have shown that the chimeric peptide R3(BΔ23-27)R/I5 suppresses food intake stimulated by an RXFP3 agonist, but has no effect on food intake when administered alone. We wanted to further investigate if R3(BΔ23-27)R/I5 on its own is able to antagonize the basal tone of the relaxin-3/RXFP3 system and therefore characterized the pharmacology of R3(BΔ23-27)R/I5 in vivo and in vitro. R3(BΔ23-27)R/I5 was intracerebroventricularly (ICV) injected in diet induced obese (DIO) Wistar rats and food intake was automatically measured during the dark phase when feeding drive is high. In our hands, R3(BΔ23-27)R/I5 alone did not have a significant effect on food intake during 24h following administration. Consistent with previous results, relaxin-3 stimulated food intake in satiated lean rats. R3(BΔ23-27)R/I5 was characterized in vitro using [(35)S]-GTPγS binding and cAMP assays, both assessing Gαi-protein mediated signalling, and dynamic mass redistribution (DMR) assays capturing the integrated cell response. R3(BΔ23-27)R/I5 showed partial agonist activity in all three functional assays. Thus, since R3(BΔ23-27)R/I5 displays partial RXFP3 agonist properties in vitro, further in vivo studies including additional tool compounds are needed to address if antagonizing relaxin-3/RXFP3 basal tone is a therapeutically relevant mechanism to regulate food intake and body weight.