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P 2 receptor: Subclassification and structure‐activity relationships
Author(s) -
Cusack Noel J.
Publication year - 1993
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/ddr.430280310
Subject(s) - agonist , ribose , chemistry , receptor , potency , stereochemistry , biochemistry , adenine nucleotide , nucleotide , pharmacology , biology , in vitro , enzyme , gene
Structure‐activity relationships (SAR) at P2 receptors that support their subclassification into at least five nucleotide receptor subtypes, P 2Z , P 2T , P 2Y , P 2U , and P 2X , are reviewed. The P 2Z receptor is the most sensitive to alterations to ATP. The adenine base, D‐ribose sugar, and 5′‐triphosphate chain are absolute requirements, but substitutions are tolerated at the C‐2 position and replacement by sulphur of an ionized phosphate oxygen leads to enhanced potency. The P 2T receptor, where ADP is the only endogenous agonist, has an absolute requirement for the adenine base, D‐ribose sugar, and a 5′‐diphosphate chain. C‐2 substitution and replacement by sulphur of an ionized oxygen is tolerated. Many analogs of AMP and of ATP are antagonists. The P 2Y receptor requires an adenine base, D‐ribose, and a 5′‐polyphosphate for maximal potency only. C‐2 substitution, and replacement of an ionized oxygen by sulphur, can enhance potency. Methylenephosphonate potencies depend on the position of the methylene group. ADP‐β‐F is a specific agonist. The P 2X receptor is least sensitive to alterations to ATP. There is no requirement for and adenine base, D‐ribose sugar, or triphosphate chain. Methylenephosphonates and some phosphorothioates have enhanced potencies. L‐AMP‐PCP is a specific agonist. Evidence from SAR for a P 2U subtype is reviewed. SAR studies are complicated by the presence of ectonucleotidases. The overall subclassification of P2 receptors is inadequate and awaits the availability of selective competitive antagonists. © 1993 Wiley‐Liss, Inc.