P₂ receptor: Subclassification and structure‐activity relationships

Abstract

Structure-activity relationships (SAR) at P2 receptors that support their subclassification into at least five nucleotide receptor subtypes, P2=, P2T, P, , , P, , , and P, , , are reviewed. The PZz 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, , receptor, where ADP i s 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 i s tolerated. Many analogs of AMP and of ATP are antagonists. The P, , 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-P-F is a specific agonist. The P, , receptor i s least sensitive to alterations to ATP. There is no requirement for an adenine base, D-ribose sugar, or triphosphate chain. Methylenephosphonates and some phosphorothioates have enhanced potencies. L-AMP-PCP i s a specific agonist. Evidence from SAR for a P, , subtype i s reviewed. SAR studies are complicated by the presence of ectonucleotidases. The overall subclassification of P2 receptors i s inadequate and awaits the availability of selective competitive antagonists. 0 1993 Wiley-Liss, Inc.

Characterization of purinoceptors mediating depolarization of rat isolated vagus nerve

“…Indeed, this high potency of a,p-methylene ATP is generally considered indicative of an action at this receptor subtype. Moreover, 2-methylthio ATP and ADP-P-S, purines that show certain selectivity for the P2y purinoceptor subtype (Burnstock & Kennedy, 1985;Cusack 1993) were relatively weak. Although it is prudent to be cautious when characterizing receptor subtypes on the basis of relative agonist potencies, taken together, these observations are consistent with the view that a P2X purinoceptor mediates the large amplitude depolarizations of the rat vagus nerve to purine nucleotides.…”

“…These data imply that one or more purinoceptors, by definition distinct from the known classical suraminsensitive P2 purinoceptors, also mediate depolarization of the rat vagus nerve. Although the suramin-sensitivity of the P2U receptor has not been reported it is unlikely that these responses are mediated via this receptor type since UTP was inactive as an agonist (Cusack, 1993). It is conceivable that these drugs activate a receptor that corresponds to the diadenosine polyphosphate binding site in rat brain synaptosomes, tentatively designated P2d by Pintor and coworkers (1993).…”

“…As with other neurotransmitters, the neuronal effects of ATP are mediated through specific extracellular receptors. These receptors for ATP have been termed purinoceptors although they may belong to a larger family of nucleotide receptors (Burnstock & Kennedy, 1985;Cusack, 1993).…”

Comparative studies on the affinities of ATP derivatives for P2X‐purinoceptors in rat urinary bladder

“…Therefore, researchers in this field are concerned to develop more selective and more potent agonists for each subtype of P2-purinoceptors, which would provide further evidence for the classification. Such work has been summarized by Cusack (1993).…”

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

“…Type P1 is responsive to adenosine and type P2 responds to ATP, ADP, UTP, UDP and not to AMP [18]. Many studies have reported that responses mediated by P2X receptors are more efficiently evoked by stable analogues of ATP such as α, β-methylene ATP than by ATP alone [28,64]. While ATP can activate both P2X and P2Y receptors, ADP interacts with the P2Y subtype receptor.…”