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Synthesis and structure‐activity relationships of pyridoxal‐6‐arylazo‐5′‐phosphate and phosphonate derivatives as P2 receptor antagonists
Author(s) -
Kim YongChul,
Camaioni Emidio,
Ziganshin Airat U.,
Ji Xiaoduo,
King Brian F.,
Wildman Scott S.,
Rychkov Alexei,
Yoburn Joshua,
Kim Heaok,
Mohanram Arvind,
Harden T. Kendall,
Boyer José L.,
Burnstock Geoffrey,
Jacobson Kenneth A.
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199810)45:2<52::aid-ddr2>3.0.co;2-v
Subject(s) - receptor , ethyl bromoacetate , ppads , chemistry , p2 receptor , stereochemistry , phosphonate , taenia coli , vas deferens , biochemistry , antagonist , biology , calcium , endocrinology , medicinal chemistry , organic chemistry
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 P2Y 1 receptors, in guinea‐pig vas deferens and bladder P2X 1 receptors, and in ion flux experiments by using recombinant rat P2X 2 receptors expressed in Xenopus oocytes. Competitive binding assay at human P2X 1 receptors in differentiated HL‐60 cell membranes was carried out by using [ 35 S]ATP‐γ‐S. A 2′‐chloro‐5′‐sulfo analog of PPADS (C 14 H 12 O 9 N 3 ClPSNa), a vinyl phosphonate derivative (C 15 H 12 O 11 N 3 PS 2 Na 3 ), and a naphthylazo derivative (C 18 H 14 O 12 N 3 PS 2 Na 2 ), were particularly potent in binding to human P2X 1 receptors. The potencies of phosphate derivatives at P2Y 1 receptors were generally similar to PPADS itself, except for the p ‐carboxyphenylazo phosphate derivative C 15 H 13 O 8 N 3 PNa and its m ‐chloro analog C 15 H 12 O 8 N 3 ClPNa, which were selective for P2X vs. P2Y 1 receptors. C 15 H 12 O 8 N 3 ClPNa was very potent at rat P2X 2 receptors with an IC 50 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 (C 14 H 12 O 8 N 3 ClPSNa) showed high potency at P2Y 1 receptors with an IC 50 of 7.23 μM. The corresponding 2,5‐disulfonylphenyl derivative was nearly inactive at turkey erythrocyte P2Y 1 receptors, whereas at recombinant P2X 2 receptors had an IC 50 value of 1.1 μM. An ethyl phosphonate derivative (C 15 H 15 O 11 N 3 PS 2 Na 3 ), whereas inactive at turkey erythrocyte P2Y 1 receptors, was particularly potent at recombinant P2X 2 receptors. Drug Dev. Res. 45:52–66, 1998. Published 1998 Wiley‐Liss, Inc.