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Comparative studies on the affinities of ATP derivatives for P 2X ‐purinoceptors in rat urinary bladder
Author(s) -
Bo Xueg,
Fischer Bilha,
Maillard Michel,
Jacobson Kenneth A.,
Burnstock Geoffrey
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb13204.x
Subject(s) - chemistry , stereochemistry , purinergic receptor , ribose , nucleotide , methylene , adenosine triphosphate , affinities , polyphosphate , allosteric regulation , biochemistry , receptor , phosphate , medicinal chemistry , enzyme , gene
1 Radioligand binding assays have been used to determine the affinities of a series of ATP derivatives with modifications of the polyphosphate chain, adenine and ribose moieties of the ATP molecule for [ 3 H]‐α,β‐methylene ATP ([ 3 H]‐α,β‐MeATP) binding sites in rat urinary bladder. 2 The replacement of the bridging oxygen in the triphosphate chain of ATP (pIC 50 = 5.58) with a methylene or imido group markedly increased the affinity (691 fold in IC 50 values for β,γ‐imidoATP, 15 fold for β,γ‐methylene ATP), and the replacement of an ionized oxygen on the γ‐phosphate with a sulphur (ATPγS) also led to increased affinity (5623 fold in IC 50 values). 3 Modifications at N 6 , N 1 , and C‐8 positions on the purine base usually reduced the affinity of ATP (a decrease of 2.8 fold in IC 50 values for N 6 ‐methylATP and 8.9 fold for 8‐bromo ATP), while the attachment of an alkylthio group to the C‐2 position greatly increased the affinity for P 2X ‐purinoceptors (from 3.5 to 98 fold increase in IC 50 values). 4 Replacement of the 3′‐hydroxyl group on the ribose with substituted amino or acylamino groups produced more potent P 2X ‐purinoceptor agonists (an increase of 447 fold in IC 50 values for 3′‐deoxy‐3′‐benzylamino ATP and 28 fold for 3′‐deoxy‐3′‐(4‐hydroxyphenylpropionyl)amino ATP. 5 Diadenosine polyphosphates (Ap[n]A) were also shown to displace the [ 3 H]‐α,β‐MeATP binding. The rank order of potency was Ap6A > Ap5A > Ap4A >> Ap3A >> Ap2A. 6 Suramin, PPADS, and reactive blue 2 could competitively displace the binding of [ 3 H]‐α,β‐MeATP to P 2X ‐purinoceptors, with pIC 50 values of 6.26, 5.35, and 6.22, respectively.