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Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline.

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

Irwin, Nigel, Flatt, Peter, Patterson, Steven and Green, BD (2010) Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline. European Journal of Pharmacology , 628 (1-3). pp. 268-273. [Journal article]

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DOI: 10.1016/j.ejphar.2009.11.022

Abstract

Much recent attention has focused on the GLP-1 receptor as a potential target for antidiabetic drugs. Enzyme resistant GLP-1 mimetics such as exenatide are now employed for the treatment of type 2 diabetes, but must be administered by injection. The present study has examined and compared the in vitro and in vivo metabolic actions of a small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB), with native GLP-1, exenatide and liraglutide. DMB significantly stimulated in vitro insulin secretion from BRIN-BD11 cells but with decreased molar potency compared to native GLP-1 or related mimetics. Administration of DMB in combination with glucose to mice significantly (P<0.05) decreased the overall glucose excursion compared to controls. Exenatide and liraglutide evoked similar (P<0.001) reductions of the overall glycaemic excursion, but were significantly (P<0.001 and P<0.05; respectively) more effective than DMB. These observations were associated with prominently (P<0.05) enhanced glucose-mediated insulin release by exenatide and liraglutide, but not by DMB. Combined injection of DMB with either liraglutide or exenatide did not substantially improve glucose-lowering or insulin-releasing responses. However, administration of DMB in combination with exendin(9-39) did not impair its glucoregulatory actions. These results provide evidence to support the development and potential use of low molecular weight GLP-1 receptor agonists for the treatment of type 2 diabetes.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:11954
Deposited By:Dr Nigel Irwin
Deposited On:15 Feb 2010 10:57
Last Modified:19 Nov 2012 15:39

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