ArticlePharmaceutical research2006
P2Y receptor mediated modulation of insulin release by a novel generation of 2-substituted-5'-O-(1-boranotriphosphate)-adenosine analogues.
Article in Pharmaceutical research, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 22 citations in OpenAlex.
- P2-type purinergic signaling in the regulation of pancreatic β-cell functional plasticity as a promising novel therapeutic approach for the treatment of type 2 diabetes?Frontiers in endocrinology · 2022Review
- Purinergic signalling in endocrine organs.Purinergic signalling · 2014Review
- Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y(1) receptor agonist.Journal of medicinal chemistry · 2012Article
- ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice.Diabetologia · 2010Article
- The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice.The Journal of clinical investigation · 2010Article
- Activation of distinct P2Y receptor subtypes stimulates insulin secretion in MIN6 mouse pancreatic beta cells.Biochemical pharmacology · 2010Article
- A novel insulin secretagogue based on a dinucleoside polyphosphate scaffold.Journal of medicinal chemistry · 2010Article
- Identification of hydrolytically stable and selective P2Y(1) receptor agonists.European journal of medicinal chemistry · 2009Article
- Purinergic receptors in the endocrine and exocrine pancreas.Purinergic signalling · 2008Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeA series of C2-substituted ATP analogues was previously shown to have potent insulin-secreting properties, yet with poor tissue-selectivity for the pancreatic beta-cell. The present study was designed to evaluate the binding profile on beta-cell membranes and the effects on insulin release and pancreatic vascular resistance of a second generation of P2Y(1) receptor agonists, based on C2-substitution of the adenosine 5'-O-(1-boranotriphosphate) scaffold. MATERIALS AND
methodsFunctional experiments were performed in the rat isolated pancreas model; binding studies with ATP-alpha-[(35)S] were performed in membrane homogenates from the rat insulinoma INS-1 cell line. The diastereoisomers of the compounds are designated by A and B.
resultsUnder 8.3 mmol l(-1) glucose, 2-methylthio-ATP-alpha-B, A isomer, induced a biphasic and concentration dependent insulin response; its maximal efficacy reaches ninefold the baseline secretion and its EC(50) is 28.1 nmol l(-1). No significant effect of this isomer was observed on vascular resistance, whereas the B isomer, which was a less potent insulin secretagogue, consistently induced a transient vasoconstriction. Interestingly, the insulin response induced by 2-methylthio-ATP-alpha-B, A isomer, was clearly glucose-dependent. This drug competes with ATP-alpha-[(35)S] binding in a complex two sites interaction model, with a K(0.5) value of 17.7 nmol l(-1). 2-Chloro-ATP-alpha-B had a similar insulin-secreting profile as 2-methylthio-ATP-alpha-B, with a lower tissue-selectivity. The non-substituted ATP-alpha-B analog, A isomer, was less potent than the C2-substituted derivatives (A isomers) and had a vasorelaxant effect.
conclusionsWe conclude that 2-methylthio-ATP-alpha-B, A isomer, is a potent and tissue-selective P2Y receptor agonist with high efficacy. Its insulin-releasing action is glucose-dependent, which gives interest to this compound as a drug candidate for treating type 2 diabetes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.