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Divergent Effects of the Purinoceptor Antagonists Suramin and Pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) on -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois

Suramin is a large naphthyl-polysulfonate compound that inhibits an array of receptors and enzymes, and it has also been reported to block currents mediated by glutamate receptors. This study shows that suramin and several structurally related compounds [8,8'-[carbonylbis(imino-3,1-phenylenecarbonylamino)]bis-(1,3,5-naphthalenetrisulfonic acid), 6Na (NF023), 8,8'-(carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino))bis-1,3,5-naphthalenetrisulfonic acid, Na (NF279), and 4,4',4'',4'''-[carbonyl-bis[imino-5,1,3-benzenetriyl-bis-(carbonylimino)]]tetrakis-benzene-1,3-disulfonic acid, 8Na (NF449)] reduce binding of [³H]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and [³H]fluorowillardiine to rat brain membranes and homomeric GluR1-4 receptors, with IC₅₀ values in the range of 5 to 180 µM. Inhibition often was less than complete at saturating drug concentrations and thus seems to be noncompetitive in nature. Pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) is a potent antagonist of purinoceptors that shares some structural elements with suramin yet is smaller than the latter. PPNDS also had potent effects on AMPA receptors (EC₅₀ value of 4 µM) but of a kind not seen with the other compounds in that it increased binding affinity for radioagonists severalfold. In addition, PPNDS slowed association and dissociation rates more than 10 times. In physiological experiments with GluR2 receptors, PPNDS at 50 µM reduced the peak current by 30 to 50% but had only small effects on other waveform aspects such desensitization and steady-state currents. This pattern of effects differentiates PPNDS from other compounds such as thiocyanate and up-modulators, which increase agonist binding by enhancing desensitization or slowing deactivation, respectively. Receptor model simulations indicate that most effects can be accounted for by assuming that PPNDS slows agonist binding/unbinding and stabilizes the bound-closed state of the receptor. By extension, suramin is proposed to stabilize the unbound state and thereby to reduce affinity for agonists. These drugs thus act through a novel type of noncompetitive antagonism.

Address correspondence to: Dr. M. Kessler, Department of Pharmacology, Southern Illinois University School of Medicine, MC 9629, 801 N. Rutledge St., Springfield, IL 62702. E-mail: mkessler{at}siumed.edu