2-thioether 5 '-O-(1-thiotriphosphate)adenosine derivatives as new insulinsecretagogues acting through P2Y-receptors

P2-Receptors (P2-Rs) represent significant targets for novel drug developme nt. P2-Rs were identified also on pancreatic B cells and are involved in in sulin secretion. Therefore, novel P2Y-R ligands, S-thioether 5'-O-phosphoro thioate adenosine derivatives (2-RS-ATP-alpha-S), were synthesized as poten tial insulin secretagogues. An efficient synthesis of these nucleotides and a facile method for separation of the chiral products are described. The e nzymatic stability of the compounds toward pig pancreas type I ATPDase was evaluated. The rate of hydrolysis of 2-hexylthio-5'-O-(1-thiotriphosphate)a de (2-hexylthio-ATP-alpha-S) isomers by ATPDase was 28% of that of ATP. Som e 2-thioether 5'-(monophosphorothioate)adenosine derivatives (2-RS-AMP-S) e xerted an inhibitory effect on ATPDase. The apparent affinity of the compou nds to P2Y(1)-R was determined by measurement of P2Y-R-promoted phospholipa se C activity in turkey erythrocyte membranes. 2-RS-ATP-alpha-S derivatives were agonists, stimulating the production ofinositol phosphates with K-0.5 values in the nanomolar range. 2-RS-AMP-S derivatives were full agonists, although 2 orders of magnitude less potent. All the compounds were more pot ent than ATP. The effect on insulin secretion and pancreatic flow rate was evaluated on isolated and perfused rat pancreas. A high increase, up to 500 %, in glucose-induced insulin secretion was due to addition of 2-hexylthio- ATP-a-S in the nanomolar concentration range, which represents 100-fold enh ancement of activity relative to ATP. 2-Hexylthio-AMP-S was 2.5 orders of m agnitude less effective.