title: Two small molecule agonists of glucagon-like peptide-1 receptor modulate the receptor activation response differently.
abstract: The glucagon-like peptide-1 receptor (GLP-1R) is a target for type 2 diabetes treatment. Due to the inconvenience of peptide therapeutics, small-molecule GLP-1R agonists have been studied. Compound 2 (6,7-dichloro-2-methylsulfonyl-2-N-tert-butylaminoquinoxaline) and compound B (4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine) have been described as small molecule, ago-allosteric modulators of GLP-1R. However, their modes of action at the GLP-1R have not been elucidated. Thus, in this study, we compared the mechanisms of action between these two compounds. When compound 2 was treated with endogenous or exogenous peptide agonists (GLP-1 and exenatide) or fragments of peptide agonists (GLP-1(9-36), Ex3, Ex4, and Ex5), the response curve of these peptide agonists shifted left without a change in maximum efficacy. In contrast, compound B potentiated the response and increased maximum efficacy. However, N-terminal truncated orthosteric antagonists including Ex7, Ex9, and Ex10, augmented the response of compound 2 at the GLP-1R but did not alter compound B activity. Intriguingly, when we co-treated compound 2 with compound B in CHO cells expressing full-length hGLP-1R or N-terminal extracellular domain-truncated GLP-1R, the activation of both types of receptors increased additively, implying that the N-terminus of the receptor is not involved in the modulation by compound agonists. We confirmed that these two compounds increased calcium influx by different patterns in CHO cells expressing GLP-1R. Taken together, our findings suggest that compounds 2 and B have different modes of action to activate GLP-1R. Further study to identify the putative binding sites will help in the discovery of orally available GLP-1R agonists.
authors.affiliation: Research Center, Dong-A Pharmaceuticals Co. Ltd., Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Ye-Hwang
authors.initials: YH
authors.lastname: Cheong
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.forename: Moon-Ho
authors.initials: MH
authors.lastname: Son
authors.forename: Bong-Kiun
authors.initials: BK
authors.lastname: Kaang
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000096:biosynthesis; D013450:Sulfones / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology
chemical_list: C517397:3-(tert-butylamino)-6,7-dichloro-2-(methylsulfonyl)quinoxaline; C570819:4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D011743:Pyrimidines; D011810:Quinoxalines; D018027:Receptors, Glucagon; D013450:Sulfones; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D002118:Calcium