Synthesis and structure-activity relationships of pyridoxal-6-arylazo-5?-phosphate and phosphonate derivatives as P2 receptor antagonists
Kim, Yong-Chul, Camaioni, Emidio, Ziganshin, Airat U., Ji, Xiao-duo, King, Brian F., Wildman, Scott S., Rychkov, Alexei, Yoburn, Joshua, Kim, Heaok, Mohanram, Arvind, Harden, T. Kendall, Boyer, Jose L., Burnstock, Geoffrey and Jacobson, Kenneth A. (1998) Synthesis and structure-activity relationships of pyridoxal-6-arylazo-5?-phosphate and phosphonate derivatives as P2 receptor antagonists. Drug Development Research, 45 (2). pp. 52-66. ISSN 0272-4391
Abstract
Novel analogs of the P2 receptor antagonist pyridoxal-5′-phosphate-6-phenylazo-2′,4′-disulfonate (PPADS) were synthesized. Modifications were made through functional group substitution on the sulfophenyl ring and at the phosphate moiety through the inclusion of phosphonates, demonstrating that a phosphate linkage is not required for P2 receptor antagonism. Substituted 6-phenylazo and 6-naphthylazo derivatives were also evaluated. Among the 6-phenylazo derivatives, 5′-methyl, ethyl, propyl, vinyl, and allyl phosphonates were included. The compounds were tested as antagonists at turkey erythrocyte and guinea-pig taenia coli P2Y1 receptors, in guinea-pig vas deferens and bladder P2X1 receptors, and in ion flux experiments by using recombinant rat P2X2 receptors expressed in Xenopus oocytes. Competitive binding assay at human P2X1 receptors in differentiated HL-60 cell membranes was carried out by using [35S]ATP-γ-S. A 2′-chloro-5′-sulfo analog of PPADS (C14H12O9N3ClPSNa), a vinyl phosphonate derivative (C15H12O11N3PS2Na3), and a naphthylazo derivative (C18H14O12N3PS2Na2), were particularly potent in binding to human P2X1 receptors. The potencies of phosphate derivatives at P2Y1 receptors were generally similar to PPADS itself, except for the p-carboxyphenylazo phosphate derivative C15H13O8N3PNa and its m-chloro analog C15H12O8N3ClPNa, which were selective for P2X vs. P2Y1 receptors. C15H12O8N3ClPNa was very potent at rat P2X2 receptors with an IC50 value of 0.82 μM. Among the phosphonate derivatives, [4-formyl-3-hydroxy-2-methyl-6-(2-chloro-5-sulfonylphenylazo)-pyrid-5- yl] methylphosphonic acid (C14H12-O8N3ClPSNa) showed high potency at P2Y1 receptors with an IC50 of 7.23 μM. The corresponding 2,5-disulfonylphenyl derivative was nearly inactive at turkey erythrocyte P2Y1 receptors, whereas at recombinant P2X2 receptors had an IC50 value of 1.1 μM. An ethyl phosphonate derivative (C15H15O11N3PS2Na3), whereas inactive at turkey erythrocyte P2Y1 receptors, was particularly potent at recombinant P2X2 receptors.
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