2-thioether 5'-O-(1-thiotriphosphate)adenosine derivatives as new insulin secretagogues acting through P2Y-Receptors.
P2-Receptors (P2-Rs) represent significant targets for novel drug development. P2-Rs were identified also on pancreatic B cells and are involved in insulin secretion. Therefore, novel P2Y-R ligands, 2-thioether 5'-O-phosphorothioate adenosine derivatives (2-RS-ATP-alpha-S), were synthesized as potential insulin secretagogues. An efficient synthesis of these nucleotides and a facile method for separation of the chiral products are described. The enzymatic stability of the compounds toward pig pancreas type I ATPDase was evaluated. The rate of hydrolysis of 2-hexylthio-5'-O-(1-thiotriphosphate)adenosine (2-hexylthio-ATP-alpha-S) isomers by ATPDase was 28% of that of ATP. Some 2-thioether 5'-(monophosphorothioate)adenosine derivatives (2-RS-AMP-S) exerted an inhibitory effect on ATPDase. The apparent affinity of the compounds to P2Y(1)-R was determined by measurement of P2Y-R-promoted phospholipase C activity in turkey erythrocyte membranes. 2-RS-ATP-alpha-S derivatives were agonists, stimulating the production of inositol 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 potent 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-alpha-S in the nanomolar concentration range, which represents 100-fold enhancement of activity relative to ATP. 2-Hexylthio-AMP-S was 2.5 orders of magnitude less effective.
Fischer
B
B
Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel. bfischer@mail.biu.ac.il
Chulkin
A
A
Boyer
J L
JL
Harden
K T
KT
Gendron
F P
FP
Beaudoin
A R
AR
Chapal
J
J
Hillaire-Buys
D
D
Petit
P
P
D000241:Adenosine / Q000031:analogs & derivatives; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001081:Apyrase / Q000378:metabolism; D004795:Enzyme Stability; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D009711:Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology; D058910:Purinergic P2 Receptor Agonists; D013440:Sulfides / Q000138:chemical synthesis / Q000494:pharmacology; D013552:Swine; D013873:Thionucleotides / Q000737:chemistry*
D007328:Insulin; D009711:Nucleotides; D058910:Purinergic P2 Receptor Agonists; D013440:Sulfides; D013873:Thionucleotides; C017817:adenosine 5'-(1-thio)triphosphate; D000255:Adenosine Triphosphate; D001081:Apyrase; D000241:Adenosine