NF449, a novel picomolar potency antagonist at human P2X1 receptors.
The antagonistic effects of the novel suramin analogue 4,4',4",4"'-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF449) were analyzed at homomeric human P2X(1) and P2X(7) receptor subtypes (hP2X(1) and hP2X(7)) heterologously expressed in Xenopus oocytes using the two-microelectrode voltage-clamp technique. At activating ATP concentrations of 1 microM (hP2X(1)) and 100 microM (hP2X(7)), IC(50) values of 0.05 nM and 40 microM were found for hP2X(1) and hP2X(7) receptors, respectively. The Schild analysis revealed a pA(2) of 10.7 at hP2X(1). Wash-in and wash-out of 10 nM NF449 were nearly complete within 16 s and 4 min, respectively, at the hP2X(1) receptor. An increase in the activating ATP concentration to 100 microM shifted the NF449 concentration-inhibition curve rightwards for the hP2X(1) receptor. NF449 decelerated activation as well as desensitization of hP2X(1). It is concluded that NF449 acts as a reversible competitive antagonist at the hP2X(1) with much higher potency at hP2X(1) than at hP2X(7) receptors. NF449 may hence be excellently suited to discriminate between both receptors in native human tissues.
Hülsmann
Martin
M
Julius-Bernstein-Institute for Physiology, Martin-Luther-University Halle, Magdeburger Strasse 6, D-06097 Halle/Saale, Germany.
Nickel
Peter
P
Kassack
Matthias
M
Schmalzing
Günther
G
Lambrecht
Günter
G
Markwardt
Fritz
F
D000818:Animals; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058469:Receptors, Purinergic P2X; D058486:Receptors, Purinergic P2X7; D014982:Xenopus laevis
C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); D001557:Benzenesulfonates; C546468:P2RX7 protein, human; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058486:Receptors, Purinergic P2X7