P-2-purinoceptor antagonists .3. Blockade of P-2-purinoceptor subtypes and ecto-nucleotidases by compounds related to suramin

Effects of suramin and five analogs or fragments of suramin were studied on contractions of the rat vas deferens elicited by alpha,beta-methylene ATP (alpha,beta-MeATP; mediated by P-2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S; mediated by P-2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. One compound, NF023, differed from suramin by removal of two p-methylbenzamido groups, whereas another, BSt101, differed from NF023 by additional removal of the three sulphonate residues from one of the terminal naphthalene rings. The compounds all shifted the concentration-response curve of alpha,beta-MeATP in the rat vas deferens to the right and simultaneously increased the maximum of the curve. Where three concentrations were tested, the Arunlakshana-Schild regression was linear, and the slope did not differ from 1. The apparent K-d values were between 1 and 3672 mu M. In the guinea-pig taenia coli, the compounds shifted the concentration-response curve of ADP beta S to the light in a parallel manner, but in the one case where three concentrations were tested, the slope of the Arunlakshana-Schild regression was lower than 1. Apparent K-d values were between 10 and 786 mu M. The removal of ATP from the medium by vas deferens tissue was decreased only by suramin, NF023 and BSt101, with IC25% values between 170 and 590 mu M. The results indicate that P-2X-purinoceptor affinity, P-2Y-purinoceptor affinity and the ecto-nucleotidase effect all increase with the size of the molecule. BSt101 resembled NF023 in potency at all three sites, indicating that the possession of a second naphthalene-trisulphonate group is not a prerequisite for relatively high affinity. NF023 is interesting because it is P-2X- versus P-2Y-selective and, in addition, the compound with the highest P-2X- versus ecto-nucleotidase-selectivity presently available.