THE ACTIVITY OF PHOSPHOROTHIOATE ANALOGS OF ATP IN VARIOUS SMOOTH-MUSCLE SYSTEMS

Abstract

Phosphorothioate analogs of ATP were tested on rat and guinea pig vas deferens, the guinea pig taenia coli and urinary bladder. Adenosine 5''0-(2-thiotriphosphate) (ATP.beta.S) was more active than adenosine 5''0(1-thiotriphosphate) (ATP.alpha.S) and ATP in producing contractile responses on the vas deferens of rat and guinea pig, and guinea pig bladder; the difference of potency was less marked for producing relaxation of the carbachol-contracted taenia coli. No differences were observed between the A and B diastereoisomers of ATP.alpha.S or ATP.beta.S. Contractions of the vas deferens produced by ATP.alpha.S were of much longer duration than those produced by ATP.beta.S. When tested against electrically-evoked twitch responses of the vas deferens, the order of potencies was reversed, with ATP being most active and ATP.beta.S least active. These inhibitory effects were blocked by 8-phenyl-theophylline. The calculated pA2 [partial arterial pressure] values of ATP, adenosine, .beta., .gamma.-methylene ATP (APPCP) and ATP.alpha.S were similar, suggesting a common site of action. The results do not reveal any stereoselectivity for the diastereoisomers of ATP phosphorothioates among the tissues tested; the observed differences of potency may be due to differences between rates of metabolism to adenosine in ATP.alpha.S and ATP.beta.S. The different response profiles to the phosphorothioates may reflect some differences of receptor mechanisms.