Studies on pyrazinoylguanidine: a novel antihypertensive, hypoglycemic and lipolytic drug intended for adjunctive use in hypertensive patients with type 2 diabetes mellitus

Vesell, Elliot S.; Beyer, Karl H.

doi:10.1016/s0300-483x(99)00213-9

Cited by 2 publications

(3 citation statements)

References 12 publications

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“…Currently we are looking into suitable rodent models of NIDDM, and one mouse model that shows promise is the strain GK lox/w + Rip-Cre developed by another group at Vanderbilt [ 25 ]. The current study shows the potential value of amiloride in improving insulin release in diabetes, and recently-developed better amiloride analogs such as pyrazinoylguanidine [ 26 , 27 ] may be good candidates for correcting the secretory defect in human diabetes.…”

Section: Resultsmentioning

confidence: 87%

Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice

2005

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BackgroundAmiloride derivatives, commonly used for their diuretic and antihypertensive properties, can also cause a sustained but reversible decrease of intracellular pH (pHi). Using dimethyl amiloride (DMA) on normal rodent pancreatic islets, we previously demonstrated the critical influence of islet pHi on insulin secretion. Nutrient-stimulated insulin secretion (NSIS) requires a specific pHi-range, and is dramatically enhanced by forced intracellular acidification with DMA. Furthermore, DMA can enable certain non-secretagogues to stimulate insulin secretion, and induce time-dependent potentiation (TDP) of insulin release in mouse islets where this function is normally absent. The present study was performed to determine whether pHi-manipulation could correct the secretory defect in islets isolated from mice with type 2 diabetes.MethodsUsing two mouse models of type 2 diabetes, we compared a) pHi-regulation, and b) NSIS with and without treatment with amiloride derivatives, in islets isolated from diabetic mice and wild type mice.ResultsA majority of the islets from the diabetic mice showed a slightly elevated basal pHi and/or poor recovery from acid/base load. DMA treatment produced a significant increase of NSIS in islets from the diabetic models. DMA also enabled glucose to induce TDP in the islets from diabetic mice, albeit to a lesser degree than in normal islets.ConclusionIslets from diabetic mice show some mis-regulation of intracellular pH, and their secretory capacity is consistently enhanced by DMA/amiloride. Thus, amiloride derivatives show promise as potential therapeutic agents for type 2 diabetes.

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Section: Resultsmentioning

confidence: 87%

Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice

2005

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“…While the 4-methyl analogue 26 was inactive, 4-fluoro substitution as in 27 gave an active compound; it is worth noting that this compound and its meta isomer were filed for patenting as antidiabetic agents. 28 The 4-trifluoromethyl analogue 28, the most potent hypotensive agent in a series of benzylguanidines, 11 was moderately active in inducing weight loss in the present work. The 4-chloro analogue 29 was more potent than galegine: p-chloro substitution also gave a potent hypoglycemic in the "formin" series.…”

Section: Introductionmentioning

confidence: 58%

“…Prior to this, a varied selection of structures, including guanidines, had been screened for antidiabetic and weight-loss activity; it is difficult to draw structure−action relationships from these published data, however, owing to the heterogeneity of the structures tested. More recently, pyrazinoylguanidine has been described as a potential treatment for diabetics who also suffer from hypertension. Importantly, we have recently reported that the effects of galegine, including the enhanced uptake of glucose and the inhibition of acetyl-CoA carboxylase, can be explained by the activation of AMP activated protein kinase (AMPK a Abbreviations: AMPK, adenosine monophosphate kinase; DIO, dietary induced obesity; ob/ob, genetically obese mice. ) .…”

Section: Introductionmentioning

confidence: 99%

Benzylguanidines and Other Galegine Analogues Inducing Weight Loss in Mice

et al. 2009

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Dimethylallylguanidine, also known as galegine, isolated from Galega officinalis, has been shown to have weight reducing properties in vivo. Substitution of the guanidine group with an N-cyano group and replacement of guanidine with amidine, pyrimidine, pyridine, or the imidazole moieties removed the weight reducing properties when evaluated in BALB/c mice. However, retention of the guanidine and replacement of the dimethylallyl group by a series of functionalized benzyl substituents was shown to exhibit, and in some cases significantly improve, the weight reducing properties of these molecules in BALB/c, ob/ob, and diet induced obesity (DIO) mice models. The lead compound identified, across all models, was 1-(4-chlorobenzyl)guanidine hemisulfate, which gave an average daily weight difference (% from time-matched controls; +/- SEM) of -19.7 +/- 1.0, -11.0 +/- 0.7, and -7.3 +/- 0.8 in BALB/c, ob/ob, and DIO models, respectively.

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Studies on pyrazinoylguanidine: a novel antihypertensive, hypoglycemic and lipolytic drug intended for adjunctive use in hypertensive patients with type 2 diabetes mellitus

Cited by 2 publications

References 12 publications

Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice

Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice

Benzylguanidines and Other Galegine Analogues Inducing Weight Loss in Mice

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