GPR40 Receptor Agonist Research Articles

Exhaustive computational studies on pyrimidine derivatives as GPR119 agonist for the development of compounds against NIDDM

BackgroundType-2 Diabetes (T2DM) is a long-term medical disorder characterized by Insulin deficiency and high blood glucose levels. Among other medications to cure T2DM, the review of the literature found that various Pyrimidine derivatives act as an agonist for G-protein-coupled receptor 119 (GPR119) was proposed to control blood glucose levels by enhancing the function of pancreatic Beta-cells and its mechanism of action with fewer adverse effects. In the present research work, In-silico investigations were carried out to investigate the potential of the Pyrimidine analog as an agonist to the protein target GPR119 receptor. We performed exhaustive molecular modeling and protein modeling methodologies such as homology modeling, and molecular docking along with various drug designing tools such as 3D-QSAR and Pharmacophore Mapping to ascertain the design of better GPR119 agonists.ResultsBased on in-depth computational studies, we designed new pyrimidine moiety and analyzed them for GPR119 receptor agonist and further explored the ADMET properties. Designed compounds were found to exhibit better-predicted activities as compared to reference compound.ConclusionsThe current research on pyrimidine derivatives, using molecular docking, 3D-QSAR and Pharmacophore mapping demonstrated that the obtained computational model has significant properties and the designed molecules and Dataset from this model, produced antidiabetic compound against the target GPR119 i.e., compound 1S, 1Z and 1D with the docking score of − 11.696, − 9.314 and − 8.721, respectively. The pharmacokinetics and drug-likeness studies revealed that these compounds may be the future candidates for the treatment of diabetes acting via the GPR119 agonist mechanism.

Structural Insight on GPR119 Agonist as Potential Therapy for Type II Diabetes: A Comprehensive Review.

Diabetes Mellitus (DM) is a long-term metabolic condition that is characterized by excessive blood glucose. DM is the third most death-causing disease, leading to retinopathy, nephropathy, loss of vision, stroke, and cardiac arrest. Around 90% of the total cases of diabetic patients have Type II Diabetes Mellitus (T2DM). Among various approaches for the treatment of T2DM. G proteincoupled receptors (GPCRs) 119 have been identified as a new pharmacological target. GPR119 is distributed preferentially in the pancreas β-cells and gastrointestinal tract (enteroendocrine cells) in humans. GPR119 receptor activation elevates the release of incretin hormones such as Glucagon-Like Peptide (GLP1) and Glucose Dependent Insulinotropic Polypeptide (GIP) from intestinal K and L cells. GPR119 receptor agonists stimulate intracellular cAMP production via Gαs coupling to adenylate cyclase. GPR119 has been linked to the control of insulin release by pancreatic β-cells, as well as the generation of GLP-1 by enteroendocrine cells in the gut, as per in vitro assays. The dual role of the GPR119 receptor agonist in the treatment of T2DM leads to the development of a novel prospective anti-diabetic drug and is thought to have decreased the probability of inducing hypoglycemia. GPR119 receptor agonists exert their effects in one of two ways: either by promoting glucose absorption by β-cells, or by inhibiting α-cells' ability to produce glucose. In this review, we summarized potential targets for the treatment of T2DM with special reference to GPR119 along with its pharmacological effects, several endogenous as well as exogenous agonists, and its pyrimidine nucleus containing synthetic ligands.

Influence of novel GPR119 agonist in combination with metformin and sitagliptin on glycemia, body weight and food intake in rats fed a high-fat diet

BACKGROUND: Metabolic syndrome and obesity are often precursors of type 2 diabetes mellitus (DM), and current recommendations indicate the advisability of early initiation of drug therapy at the stage of prediabetes. Drugs with incretin activity are one of the priority groups for monotherapy of type 2 diabetes in the onset of the disease, and certain drugs are used to treat obesity. GPR119 agonists increase the secretion of endogenous incretins, and their effectiveness in the treatment of type 2 diabetes and obesity in mono- and combination therapy is currently being actively studied.
 AIM. To evaluate of the effect of administration of a GPR119 receptor agonist, its combination with metformin or sitagliptin on body weight, food intake and glycemia in rats under a high-calorie diet.
 MATERIALS AND METHODS: The study was conducted on 56 outbred female rats aged 78 months and an initial weight of 305320 g. Compound ZB-16 is a highly active GPR119 receptor agonist (EC50 = 7 nM). For 12 weeks, the animals were kept on a high-fat and carbohydrate diet and at the same time received the compound ZB-16, metformin and sitagliptin, or its combination (ZB-16 + metformin and ZB-16 + sitagliptin). During the experiment, the weight of the animals, the mass of feed eaten, as well as the level of glycemia after 6 hours of fasting and with an oral glucose load were assessed.
 RESULTS: In animals of the control group that were on a high-calorie and fatty diet for 12 weeks, an increase in body weight, glycemia and a decrease in the rate of glucose utilization were observed. The introduction of the GPR119 agonist (ZB-16) for 12 weeks led to a significant reduction in the amount of food consumed, limited weight gain and prevented the development of carbohydrate metabolism disorders. The addition of sitagliptin and especially metformin to therapy with the GPR119 agonist significantly increased the effectiveness of therapy compared to the control group, which was expressed in the normalization of animal body weight and glycemia (p 0.05).
 CONCLUSIONS: The introduction of a combination of the GPR119 agonist (compound ZB-16) with metformin and sitagliptin is more effective than monotherapy in terms of weight gain, food intake, and also prevents the development of carbohydrate metabolism disorders in animals when kept on a high-fat and carbohydrate diet.

Психоневрологические нарушения у животных с ишемией головного мозга на фоне сахарного диабета и их коррекция новым агонистом GPR119 и его комбинациями с метформином и цитиколином

Сахарный диабет (СД) 2 типа значительно повышает риск развития инсульта и выбор гипогликемической терапии может оказать влияние не только на вероятность развития, но и на тяжесть течения нарушения мозгового кровообращения (НМК). Цель: оценить влияние комбинированного введения агониста GPR119 с метформином и цитиколином на выраженность психоневрологических нарушений у животных с НМК на фоне СД. Методика. Исследование проведено на крысах линии Wistar, которым моделировали фокальную ишемию ГМ на фоне 28 дневного стрептозотоцин-никотинамид-индуцированного СД. Агонист рецептора GPR119 (дипиарон) и его комбинацию с метформином вводили с первого дня развития СД, а цитиколин - после моделирования НМК. Психоневрологические нарушения оценивались с использованием шкал «Combs & D’Alecy» и «Garcia», и тестов «Открытое поле», «Ротарод», УРПИ и ТЭИ. Результаты и обсуждение. Введение метформина приводило к нормализации уровня гликемии, но не снижало выраженность неврологического дефицита при последующем моделировании НМК. По сравнению с контролем в группах, получавших дипиарон и в большей степени его комбинацию с метформином, помимо улучшения контроля гликемии наблюдалось значительное снижение объема инфаркта и отёка мозга, а также выраженности психоневрологических нарушений у выживших животных (p<0,05). Введение цитиколина без гипогликемической терапии не приводило к снижению уровня неврологического дефицита по сравнению с контрольной группой, при этом добавление цитиколина к гипогликемической терапии значимо не снижало тяжесть течения НМК. Заключение. Комбинированное введение агониста GPR119 и метформина животным с экспериментальной ишемией ГМ на фоне СД значительно повышает терапевтический потенциал обоих препаратов, обеспечивая лучший контроль уровня гликемии и снижая выраженность психоневрологического дефицита при моделировании НМК. Type 2 diabetes mellitus (DM2) significantly increases the risk of stroke, and the choice of hypoglycemic therapy may influence not only a probability of stroke but also severity of cerebrovascular disease. Objective: To evaluate the effect of combination treatment with a GPR119 agonist, metformin and citicoline on severity of neurological disorders in animals with stroke and diabetes. Cerebral ischemia was modeled by intraluminal occlusion of the middle cerebral artery (OMCA). Methods. The study was performed on Wistar rats with 28-day streptozotocin-nicotinamide-induced diabetes. The GPR119 receptor agonist (dipiaron) and its combination with metformin were administered starting from the first day of DM, and citicoline was administered after the induction of brain ischemia. Behavioral and neurological disorders were evaluated using the Combs & D’Alecy and Garcia scales, and the open field, Rotarod, and active and passive avoidance tests. Results. The metformin treatment normalized glycemia but did not alleviate severity of the neurological deficit induced by subsequent OMCA. The groups treated with dipiaron and its combination with metformin, in addition to improved glycemic control, showed significant decreases in brain infarction volume and edema and the severity of neurological disorders in surviving animals compared to the control (p<0.05). Administration of citicoline without the hypoglycemic therapy reduced the neurological deficit in comparison with the control group. Addition of citicoline to the hypoglycemic therapy did not significantly reduce the severity of brain ischemia. Conclusion. The combination treatment of animals with brain ischemia and diabetes with the GPR119 agonist and metformin significantly enhanced the therapeutic potential of both drugs evident as a better glycemic control and alleviated severity of the neurological deficit following OMCA.

Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16

This article is to highlight the chemical properties and primary pharmacology of novel GPR119 agonist ZB-16 and its analogs, which were rejected during the screening. Experiments were performed in vitro (specific activity, metabolism and cell toxicity) and in vivo (hypoglycemic activity and pharmacokinetics). ZB-16 exhibits nanomolar activity (EC50 = 7.3–9.7 nM) on target receptor GPR119 in vitro associated with hypoglycemic activity in vivo. In animals with streptozotocin-nicotinamide induced type 2 diabetes mellitus (STZ-NA T2D) daily oral dose of ZB-16 (1 mg/kg) or sitagliptin (10 mg/kg) for 28 days resulted in the reduction of blood glucose levels. The effects of ZB-16 were comparable to the hypoglycemic action of sitagliptin. ZB-16 demonstrated relatively low plasma exposition, high distribution volume, mild clearance and a prolonged half-life (more than 12 h). The present study demonstrates that the targeted search for selective GPR119 receptor agonists is a well-founded approach for developing novel drugs for the therapy of T2D. Based on the combination of high in vitro activity (compared to competitor standards), a useful ADME profile, distinct hypoglycemic activity which is comparable to the efficacy of sitagliptin in rats with experimental T2D, and the acceptable pharmacokinetic profile, we recommend the ZB-16 compound for further research.

Influence of novel GPR119 agonist in combination with metformin and sitagliptin on lipid profile and endothelial function in rats fed a high-fat diet

Aim. Study the influence of novel GPR119 agonist in combination with metformin and sitagliptin on lipid profile and endothelial function in rats fed a high-fat diet. Methods and Results. The study was carried out on female rats with an initial weight of 305-320 g. For 12 weeks, rats fed a high-fat diet, and simultaneously started treatment with GPR119 receptor agonist - ZB-16, metformin and sitagliptin or its combinations. After 12 weeks rats were weighed and lipid profile, cerebral blood flow and endothelial function were evaluated. Preventive administration of GPR119 agonist in combination with metformin and sitagliptin prevents weight gain, reduces the severity of lipid metabolism disorders and restores the endothelial function in rats fed a high-fat diet (p<0.05).

Combination of APD668, a G protein-coupled receptor 119 agonist with linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in a murine model of non-alcoholic steatohepatitis with diabetes.

Non-alcoholic steatohepatitis (NASH) is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, and hepatocyte injury with or without fibrosis. In this study, we explored the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor, on the progression of steatohepatitis in a murine model of NASH with diabetes. A novel NASH model with diabetes was generated by administration of streptozotocin injection to neonatal C57BL/6 mice (2-3daysold) combined with a high-fat diet feeding from the age of 4weeks. The plasma biochemical parameters, oxidative stress, inflammation and histopathological changes were assessed. APD668 alone showed reduction in plasma glucose (- 39%, P < 0.05) and triglyceride level (- 26%) whereas a combined treatment of APD668 with linagliptin resulted in a more pronounced reduction in plasma glucose (- 52%, P < 0.001) and triglyceride (- 50%, P < 0.05) in NASH mice. In addition, co-administration of APD668 with linagliptin demonstrated a significant decrease in hepatic triglyceride, NAS score, hepatic TBARS and hepatic TNF-α in NASH mice with diabetes. These findings suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of NASH.

Co-administration of APD668, a G protein-coupled receptor 119 agonist and linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in mice fed on a high trans-fat diet

Non-Alcoholic SteatoHepatitis (NASH) is the more severe form of Non-Alcoholic Fatty Liver Disease (NAFLD) and is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, hepatocyte injury with or without fibrosis. Recently, GPR119 receptor has emerged as a novel therapeutic target for the treatment of dyslipidemia and non-alcoholic steatohepatitis. In the present study, we investigated the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor on the progression of steatohepatitis in mice fed on a high trans-fat diet. In this study, monotherapy with either APD668 or linagliptin caused a reduction in the levels of ALT, AST, glucose, cholesterol and epididymal fat mass but the effect was more pronounced upon treatment with combination of both drugs.On the other hand, combined treatment of APD668 with linagliptin demonstrated a non-significant additive effect in reduction of hepatic triglyceride (−78%) and cholesterol (−56%) compared to monotherapy groups. Moreover, co-administration of APD668 and linagliptin resulted in enhanced levels of active GLP-1 with additional benefit of significant synergistic decrease in body weight gain (−19%) in mice. We speculated that the enhanced effect observed with the combination treatment could be due to either 1) direct activation of GPR119 receptors present in liver and intestine or 2) enhanced active GLP-1 levels or 3) decreased degradation of GLP-1 in-vivo through DPPIV inhibition. Therefore, these findings clearly suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of non-alcoholic steatohepatitis.

Parameterization of the GPR119 Receptor Agonist AR231453.

The GPR119 receptor is a class A G protein-coupled receptor expressed mainly in pancreatic beta cells. Since GPR119 receptor activation ameliorates Type 2 Diabetes through an increase in glucose-dependent insulin release, the development of new GPR119 receptor agonists would be worthwhile. A better understanding of the way agonists interact with the receptor would help to design better ligands for the receptor. It also would help to better understand the agonist mechanism of action. An understanding of how agonists interact with the receptor can be acquired using molecular dynamics simulations, which cannot be performed without having force field parameters for the ligand molecule. This study presents the development of CHARMM force field parameters for AR231453, the prototypical first potent and orally available GPR119 agonist, using the Force Field Tool Kit. The parameters are validated through Normal Mode Analysis calculations and molecular dynamics simulations in combination with infrared spectroscopy. © 2017 Wiley Periodicals, Inc.

INFLUENCE OF GPR119 RECEPTOR AGONIST ON INSULIN PRODUCTION AND INSULIN RESISTANCE IN INTACT RATS AND RATS WITH EXPERIMENTAL DIABETES MELLITUS

Hypoglycemic action of ZB-16, a novel GPR119 receptor agonist, is incretin-mediated and involves increased secretion of insulin in response to a glucose load. The administration of ZB-16 reduces glucose tolerance and insulin resistance index in rats with type 2 diabetes mellitus.

Гиполипидемическое, антиоксидантное и эндотелиопозитивное действие нового агониста рецептора GPR 119 соединения ZB-16 при экспериментальном сахарном диабете

В исследовании на животных с экспериментальным сахарным диабетом (ЭСД) показано влияние 2-недельного введения агониста GPR119 (соединения ZB-16) на функцию эндотелия, обмен глюкозы и липидов (содержание общего холестерина, триглицеридов, липопротеидов низкой и высокой плотности), процессы перекисного окисления липидов. Установлено, что в группе животных с ЭСД, помимо устойчивой гипергликемии, наблюдается снижение эндотелийзависимой вазодилатации и активности антиоксидантной системы, а также повышение содержания липопротеидов низкой плотности и дислипидемического индекса. Соединение ZB-16 (1 мг/кг per os) снижает эндотелиальную дисфункцию у животных с ЭСД типа (повышая эндотелийзависимую вазодилатацию на 83 % по сравнению с контрольной группой, р ≤ 0,05), оказывает умеренное антиоксидантное действие (снижая содержание ТБК-активных продуктов на 30 % по сравнению с контрольной группой без лечения, p ≤ 0,05) и способствует нормализации показателей липидного обмена.

Development of Large-Scale Routes to Potent GPR119 Receptor Agonists

Practical and scalable syntheses were developed that were used to prepare multikilogram batches of GSK1292263A (1) and GSK2041706A (15), two potent G protein-coupled receptor 119 (GPR119) agonists. Both syntheses employed relatively cheap and readily available starting materials, and both took advantage of an SNAr synthetic strategy.

Design and synthesis of 1H-pyrazolo[3,4-c]pyridine derivatives as a novel structural class of potent GPR119 agonists

Design and synthesis of a novel class of 1H-pyrazolo[3,4-c]pyridine GPR119 receptor agonists are described. Lead compound 4 was identified through the ligand-based drug design approach. Modification of the left-hand aryl group (R1) and right-hand piperidine N-capping group (R2) led to the identification of compound 24 as a single-digit nanomolar GPR119 agonist.

Influence of novel GPR119 receptor agonist on plasma glucose and insulin level, as well as structural changes of pancreas islets in rats with experimental type 2 diabetes

Background. GPR119 receptor is a promising target for novel antidiabetic drugs development because of its agonists in addition to hypoglycemic effects have cytoprotective effect on beta cells.Aim — to assess the effect of the novel GPR119 receptor agonist and sitagliptin on carbohydrate metabolism and morphological structure of the pancreas in animals with experimental type 2 diabetes.Material and methods. The study was performed in Wistar rats with streptozotocin-nicotinamide-induced diabetes. Serum insulin was determined by ELISA (Rat Insulin, (INS) ELISA Kit, 96 CSB). Immunohistochemical studies were performed using mouse monoclonal antibodies to insulin (clone 1G4, GeneTex) with determination of the absolute and relative area of immunopositive material (beta-cells) of the pancreatic islets.Results. 28-day treatment of animals with diabetes by GPR119 receptor agonist — ZB-16 (dipiaron) (1 mg/kg, per os, daily) and an inhibitor of the DPP-4 (sitagliptin) led to a reduction of fasting hyperglycemia and improve its glucose tolerance and enhance basal and stimulated insulin secretion relative to the control without treatment. Morphometric assessment of islets revealed that animals treated with the ZB-16 and sitagliptin have significantly higher absolute and relative islets area, as well as the perimeter of the insulin-positive material compared to islets of rats without treatment.Conclusion. Course administration of GPR119 receptor agonist to animals with streptozotocin-nicotinamide-induced diabetes has a pronounced antidiabetic effect consists in reducing fasting plasma glucose, improve glucose utilization, increase basal and stimulated insulin secretion, as well as increasing the area of the insulin-positive material in islets. Antidiabetic action of novel GPR119 receptor agonist, was comparable to that of sitagliptin.

GPR40 receptor activation leads to CREB phosphorylation and improves cognitive performance in an Alzheimer’s disease mouse model

Alzheimer’s disease (AD) is a very complex neurodegenerative disorder as neuronal loss is a prominent and initial feature of AD. This loss correlates with cognitive deficits more closely than amyloid load. GPR40 receptor belongs to the class of G-protein coupled receptors, is expressed in wide parts of the brain including the hippocampus which is involved in spatial learning and memory. Till now, there are few studies investigating the functional role of GPR40 in brain. In this study, we evaluated the functional role of GPR40 receptor in the A-beta AD mice model. Administration of Aβ1–42 (410pmol) intracerebroventricularly (i.c.v.) once at the beginning of experiment significantly impaired cognitive performance (in step-through passive test), the ability of spatial learning and memory in (Morris water maze test), working memory, attention, anxiety in (Novel object recognition test), and spatial working and reference-memory in (Hole board discrimination test) compared with the control group. The results revealed that GPR40 receptor treatment groups significantly ameliorated model mice cognitive performance. All GPR40 receptor agonist GW9508, treatment groups enhanced the learning and memory ability in Step-through passive test, Morris water maze test, Hole board discrimination test, Novel object recognition test. Furthermore, we have observed that activation of GPR40 receptor provoked the phosphorylation of the cAMP response element binding protein (CREB) and significant increase in neurotropic factors including brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrohin-4 (NT-4) in mouse hippocampal neurons and contribute to neurogenesis. These results suggest that GPR40 is a suitable therapeutic candidate for neurogenesis and neuroprotection in the treatment and prevention of AD.

Asymmetric synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives via sequential palladium and copper catalysis.

We present a full account detailing the development of a sequential catalysis strategy for the synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives. A palladium-catalyzed cross coupling of terminal alkyne donors with acetylenic ester, ketone, and sulfone acceptors generates stereodefined enynes in high yield. These compounds are engaged in an unprecedented, regio- and enantioselective copper-catalyzed conjugate reduction. The process exhibits a high functional group tolerance, and this enables the synthesis of a broad range of chiral products from simple, readily available alkyne precursors. The utility of the method is demonstrated through the elaboration of the chiral β-alkynyl products into a variety of different molecular scaffolds. Its value in complex molecule synthesis is further validated through a concise, enantioselective synthesis of AMG 837, a potent GPR40 receptor agonist.

Gut Hormone Pharmacology of a Novel GPR119 Agonist (GSK1292263), Metformin, and Sitagliptin in Type 2 Diabetes Mellitus: Results from Two Randomized Studies

GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25–800 mg; n = 45) or multiple doses (100–600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼five-fold compared with placebo, reaching peak concentrations of ∼50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides.Trial Registration:Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621

Exploring the Binding Site of the G Protein-Coupled Receptor GPR119 Model using a Pair of Diastereomers with Opposing Action

GPR119 is a Class A (rhodopsin-like) G-protein coupled receptor that has insulin-regulating activity. GPR119 agonists stimulate glucose-dependent insulin secretion in vitro and lower elevated blood glucose in vivo. Hence, the GPR119 receptor has emerged as an important target for the treatment of type 2 diabetes. An initial GPR119 homology model was constructed using the adenosine A2A receptor crystal structure bound to an antagonist at 2.6A resolution (PDB id: 3EML) as the template. The preliminary model was refined by exploring the flexibility of individual helices using the Monte Carlo/simulated annealing method, Conformational Memories (CM). CM employs multiple Monte Carlo/simulated annealing random walks, exploring peptide and protein dihedral conformational space. A pair of previously reported diastereomers, one of which acts as a GPR119 receptor agonist and the other as an antagonist, were docked into the active (R∗) and inactive (R) receptor models. The putative binding site of the preliminary R model starts between the top of transmembrane helices (TMHs) 2 and 7 and spans the bundle in a shallow diagonal direction, almost perpendicular to the TMH region. The floor of the binding site is between TMHs 3, 5 and 6 at the level of F234(6.44) (middle of the TMH bundle). W238(6.48) (χ1 = g+) places its bulk between TMHs 6 and 7. The only charged amino acid that is accessible to the binding site, R81(3.28), was used as the primary interaction site for both compounds. The GPR119 R∗ state binding site is more vertical compared to the R state and somewhat deeper because of a χ1 rotamer change of W238(6.48) to a trans conformation in the R∗ state, which places its bulk between TMHs 5 and 6.

Iridium‐Catalyzed Enantioselective Allylic Alkynylation

No leaving group needed: With an Ir(P,olefin) complex as catalyst, the direct enantioselective allylic alkynylation of secondary allylic alcohols with potassium alkynyltrifluoroborates as alkynylating reagents has been achieved. High levels of enantioselectivity and high yields were achieved with this operationally easy and robust protocol, the use of which was demonstrated in the synthesis of GPR40 receptor agonist AMG 837. cod = 1,5-cyclooctadiene.

Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion

We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.