Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Drug Dev Res
1998 Oct 01;452:52-66. doi: 10.1002/(SICI)1098-2299(199810)45:2<52::AID-DDR2>3.0.CO;2-V.
Show Gene links
Show Anatomy links
Synthesis and Structure-Activity Relationships of Pyridoxal-6-arylazo-5'-phosphate and Phosphonate Derivatives as P2 Receptor Antagonists.
Kim YC
,
Camaioni E
,
Ziganshin AU
,
Ji XD
,
King BF
,
Wildman SS
,
Rychkov A
,
Yoburn J
,
Kim H
,
Mohanram A
,
Harden TK
,
Boyer JL
,
Burnstock G
,
Jacobson KA
.
???displayArticle.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 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.
???displayArticle.pubmedLink???
22922976
???displayArticle.pmcLink???PMC3424000 ???displayArticle.link???Drug Dev Res ???displayArticle.grants???[+]
Abbracchio,
Purinoceptors: are there families of P2X and P2Y purinoceptors?
1994, Pubmed
Abbracchio,
Purinoceptors: are there families of P2X and P2Y purinoceptors?
1994,
Pubmed
Boyer,
Differential effects of P2-purinoceptor antagonists on phospholipase C- and adenylyl cyclase-coupled P2Y-purinoceptors.
1994,
Pubmed
Boyer,
Kinetics of activation of phospholipase C by P2Y purinergic receptor agonists and guanine nucleotides.
1989,
Pubmed
Boyer,
Competitive and selective antagonism of P2Y1 receptors by N6-methyl 2'-deoxyadenosine 3',5'-bisphosphate.
1998,
Pubmed
Brake,
New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor.
1994,
Pubmed
,
Xenbase
Brown,
PPADS: an antagonist at endothelial P2Y-purinoceptors but not P2U-purinoceptors.
1995,
Pubmed
Buell,
P2X1 receptor activation in HL60 cells.
1996,
Pubmed
Bültmann,
Evaluation of P2-purinoceptor antagonists at two relaxation-mediating P2-purinoceptors in guinea-pig taenia coli.
1996,
Pubmed
Burnstock,
Purinergic receptors: their role in nociception and primary afferent neurotransmission.
1996,
Pubmed
Burnstock,
Structure Activity Relationships for Derivatives of Adenosine-5'-Triphosphate as Agonists at P(2) Purinoceptors: Heterogeneity Within P(2X) and P(2Y) Subtypes.
1994,
Pubmed
Burnstock,
P2 purinoceptors: historical perspective and classification.
1996,
Pubmed
Camaioni,
Deoxyadenosine bisphosphate derivatives as potent antagonists at P2Y1 receptors.
1998,
Pubmed
Communi,
Cloning of a human purinergic P2Y receptor coupled to phospholipase C and adenylyl cyclase.
1997,
Pubmed
Communi,
Receptors responsive to extracellular pyrimidine nucleotides.
1997,
Pubmed
Di Virgilio,
P2 purinoceptors in the immune system.
1996,
Pubmed
Fredholm,
Towards a revised nomenclature for P1 and P2 receptors.
1997,
Pubmed
Greco,
Functional expression of a P2T ADP receptor in Xenopus oocytes injected with megakaryocyte (CMK 11-5) RNA.
1997,
Pubmed
,
Xenbase
Harden,
Phosphoinositide hydrolysis by guanosine 5'-[gamma-thio]triphosphate-activated phospholipase C of turkey erythrocyte membranes.
1988,
Pubmed
Hourani,
P2T purinoceptors: ADP receptors on platelets.
1996,
Pubmed
Hullar,
Pyridoxal phosphate. I. Phosphonic acid analogs of pyridoxal phosphate. Synthesis via Wittig reactions and enzymic evaluation.
1969,
Pubmed
Humphrey,
New insights on P2X purinoceptors.
1995,
Pubmed
Inoue,
Implication of ATP receptors in brain functions.
1996,
Pubmed
Inscho,
Purinoceptor-mediated regulation of the renal microvasculature.
1996,
Pubmed
Jacobson,
A pyridoxine cyclic phosphate and its 6-azoaryl derivative selectively potentiate and antagonize activation of P2X1 receptors.
1998,
Pubmed
,
Xenbase
King,
Effects of extracellular pH on agonism and antagonism at a recombinant P2X2 receptor.
1997,
Pubmed
,
Xenbase
Lambrecht,
PPADS, a novel functionally selective antagonist of P2 purinoceptor-mediated responses.
1992,
Pubmed
McLaren,
Investigation of the actions of PPADS, a novel P2x-purinoceptor antagonist, in the guinea-pig isolated vas deferens.
1994,
Pubmed
North,
Nucleotide receptors.
1997,
Pubmed
Rongen,
Cardiovascular pharmacology of purines.
1997,
Pubmed
Schachter,
Second messenger cascade specificity and pharmacological selectivity of the human P2Y1-purinoceptor.
1996,
Pubmed
Trezise,
P2 purinoceptor antagonist properties of pyridoxal-5-phosphate.
1994,
Pubmed
Williams,
Challenges in developing P2 purinoceptor-based therapeutics.
1996,
Pubmed
Windscheif,
Vasoconstrictor and vasodilator responses to various agonists in the rat perfused mesenteric arterial bed: selective inhibition by PPADS of contractions mediated via P2x-purinoceptors.
1994,
Pubmed
Windscheif,
Two different inhibitory effects of pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid on adenosine diphosphate-induced human platelet aggregation.
1995,
Pubmed
Windscheif,
Inhibitory action of PPADS on relaxant responses to adenine nucleotides or electrical field stimulation in guinea-pig taenia coli and rat duodenum.
1995,
Pubmed
Ziganshin,
Selective antagonism by PPADS at P2X-purinoceptors in rabbit isolated blood vessels.
1994,
Pubmed
Ziganshin,
PPADS selectively antagonizes P2X-purinoceptor-mediated responses in the rabbit urinary bladder.
1993,
Pubmed
