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Activity of novel adenine nucleotide derivatives as agonists and antagonists at recombinant rat P2X receptors
Author(s) -
Brown Sean G.,
King Brian F.,
Kim YongChul,
Jang Soo Yeon,
Burnstock Geoffrey,
Jacobson Kenneth A.
Publication year - 2000
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 - 10.1002/1098-2299(200004)49:4<253::aid-ddr4>3.0.co;2-1
Subject(s) - recombinant dna , receptor , chemistry , agonist , pharmacology , nucleotide , biochemistry , biology , gene
The effects of structural modifications of adenine nucleotides previously shown to enhance either agonist (2‐thioether groups) or antagonist (additional phosphate moieties at the 3′‐ or 2′‐position) properties at P2Y 1 receptors were examined at recombinant rat P2X 1 , P2X 2 , P2X 3 , and P2X 4 receptors expressed in Xenopus oocytes. The potency of P2Y 1 agonists HT‐AMP (2‐(hexylthio)adenosine‐5′‐monophosphate) and PAPET (2‐[2‐(4‐aminophenyl)ethylthio]adenosine‐5′‐triphosphate) was examined at P2X receptors. Both nucleotides showed a preference for the Group I (α,β‐meATP‐sensitive, fast‐inactivating) P2X subunits. HT‐AMP was 5‐fold more potent than ATP at P2X 3 receptors and a partial agonist at all except P2X 2 receptors, at which it was a full agonist. The efficacy of HT‐AMP was as low as 23% at P2X 4 receptors. PAPET was a weak partial agonist at rat P2X 4 receptors and a nearly full agonist at the other subtypes. At rat P2X 3 receptors, PAPET was more potent than any other known agonist (EC 50 = 17 ± 3 nM). MRS 2179 ( N 6 ‐methyl‐2′‐deoxyadenosine 3′, 5‐bisphosphate, a potent P2Y 1 receptor antagonist) inhibited ATP‐evoked responses at rat P2X 1 receptors with an IC 50 value of 1.15 ± 0.21 μM. MRS 2179 was a weak antagonist at rat P2X 3 receptors, with an IC 50 value of 12.9 ± 0.1 μM, and was inactive at rat P2X 2 and P2X 4 receptors. Thus, MRS 2179 was 11‐fold and 130‐fold selective for P2Y 1 receptors vs. P2X 1 and P2X 3 receptors, respectively. MRS 2209, the corresponding 3′‐deoxy‐2′‐phosphate isomer, was inactive at rat P2X 1 receptors, thus demonstrating its greater selectivity as a P2Y 1 receptor antagonist. Various adenine bisphosphates in the family of MRS 2179 containing modifications of either the adenine (P2Y 1 antagonists with 2‐ and 6‐substitutions), the phosphate (a 3′,5′‐cyclic diphosphate, inactive at P2Y 1 receptors), or the ribose moieties (antagonist carbocyclic analogue), were inactive at both rat P2X 1 and P2X 3 receptors. An anhydrohexitol derivative (MRS 2269) and an acyclic derivative (MRS 2286), proved to be selective antagonists at P2Y 1 receptors, since they were inactive as agonist or antagonist at P2X 1 and P2X 3 receptors. Drug Dev. Res. 49:253–259, 2000. Published 2000 Wiley‐Liss, Inc.