title: Stimulation of Glucose-Dependent Insulin Secretion by a Potent, Selective sst3 Antagonist.
abstract: This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic β-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3 knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in treating type 2 diabetes mellitus.
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Reynalda
authors.initials: R
authors.lastname: de Jesus
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Shuwen
authors.initials: S
authors.lastname: He
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Dobbelaar
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Bradley
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Kwei-Lan
authors.initials: KL
authors.lastname: Tsao
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Dorina
authors.initials: D
authors.lastname: Trusca
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Cai
authors.initials: C
authors.lastname: Li
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: Wu
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Nargund
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
keywords: glucose-stimulated insulin secretion; somatostatin; sst3; type 2 diabetes