Abstract
Effects of suramin and five analogs or fragments of suramin were studied on contractions of the rat vas deferens elicited by α,β-methylene ATP (α,β-McATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5′-O-(2-thiodiphosphate) (ADPβS; mediated by P2Y-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 α,β-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 μM. In the guinea-pig taenia coli, the compounds shifted the concentration-response curve of ADPβS to the right 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 μM. 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 μM.
The results indicate that P2X-purinoceptor affinity, P2Y-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 P2X- versus P2Y-selective and, in addition, the compound with the highest P2X- versus ecto-nucleotidase-selectivity presently available.
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Bültmann, R., Wittenburg, H., Pause, B. et al. P2-purinoceptor antagonists: III. Blockade of P2-purinoceptor subtypes and ecto-nucleotidases by compounds related to suramin. Naunyn-Schmiedeberg's Arch Pharmacol 354, 498–504 (1996). https://doi.org/10.1007/BF00168442
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DOI: https://doi.org/10.1007/BF00168442