title: P2Y receptor mediated modulation of insulin release by a novel generation of 2-substituted-5'-O-(1-boranotriphosphate)-adenosine analogues.
abstract: OBJECTIVE
  A 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.
  
  
  METHODS
  Functional 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.
  
  
  RESULTS
  Under 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Centre de Pharmacologie et Biotechnologie pour la Santé, CNRS UMR 5160, Faculté de Pharmacie, 15 Avenue Charles Flahault, BP 14491, 34093, Montpellier cedex 5, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Farret
authors.forename: Romain
authors.initials: R
authors.lastname: Filhol
authors.forename: Nathalie
authors.initials: N
authors.lastname: Linck
authors.forename: Michèle
authors.initials: M
authors.lastname: Manteghetti
authors.forename: Jacques
authors.initials: J
authors.lastname: Vignon
authors.forename: René
authors.initials: R
authors.lastname: Gross
authors.forename: Pierre
authors.initials: P
authors.lastname: Petit
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001880:Boranes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058472:Receptors, Purinergic P2Y1; D013873:Thionucleotides / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D001880:Boranes; D007328:Insulin; C546384:P2ry1 protein, rat; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D013873:Thionucleotides; C017817:adenosine 5'-(1-thio)triphosphate; D000255:Adenosine Triphosphate; C008501:2-methylthio-ATP