Studies on the stereoselectivity of the P₂‐purinoceptor

Abstract

1ATP, 2-chloro-ATP, 2-methylthio-ATP, and their unnatural L-enantiomers, were synthesized and their effects tested on the guinea-pig taenia coli and urinary bladder, and the stimulated frog ventricle. 2 The potent P2-purinoceptor agonists, 2-chloro-ATP and 2-methylthio-ATP were, respectively, 30 and 200 times more effective than ATP in relaxing the guinea-pig taenia, but approximately as effective as ATP in contracting the guinea-pig bladder and augmenting the force of contraction of the frog ventricle. 3 A high degree of stereoselectivity was observed for relaxations of the guinea-pig taenia coli produced by theP2-purinoceptoragonists, and 2-methylthio-ATP was over 700 times more effective than its L-enantiomer. In contrast, stereoselectivity for contraction of the guinea-pig bladder was observed only at low concentrations with each pair of enantiomers, and a similar low stereoselectivity was displayed by the frog ventricle. 4 These results show that P2-purinoceptors mediating inhibitory responses in the guinea-pig taenia coli can show a high degree of stereoselectivity, while P2-purinoceptors mediating excitatory responses in the guinea-pig bladder and in the frog ventricle show little stereoselectivity. 5 The partial stereoselectivity of the P2-purinoceptor in smooth muscle contrasts with the absolute stereospecificity of P, -purinoceptors for adenosine on smooth muscle and autonomic nerve terminals and the absolute stereospecificity of the receptor for ADP on the human platelet.

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

“…2-MeSATP has been known for a long time to be a potent P2y-purinoceptor agonist (Gough et al, 1973;Satchell & Maguire, 1975;Burnstock et al, 1983) although it can also activate P2x-purinoceptors at a higher concentration (Howson et al, 1988;Theobald, 1992). Further modifications on the C-2 position produced 2-HeSATP, 2-CyaHeSATP, 2-phenylethylthio ATP, and 2-(2-p-nitrophenylethyl)thio ATP, which did not show significantly increased efficacy on P2Y-purinoceptors, while the potency on P2x-purinoceptors have been greatly enhanced (Fischer et al, 1993).…”

P2‐purinoceptors of two subtypes in the rabbit mesenteric artery: reactive blue 2 selectively inhibits responses mediated via the P2y‐ but not the P2x‐purinoceptor

“…A rank potency order of a,fi-methylene, 0,ymethylene ATP > ATP = 2-methylthio ATP is indicated in these tissues. In the guinea-pig taenia coli (Satchell & Maguire, 1975;Maguire & Satchell, 1979;Burnstock et al, 1983), the rabbit portal vein (Kennedy & Burnstock, 1985b), the pig and rat aorta (Martin et al, 1985a;White et al, 1985) and the rat femoral artery , P2-purinoceptors mediate relaxations. A rank order of potency in these tissues is 2-methylthio ATP > ATP > a,,-methylene ATP, ,y-methylene ATP.…”

“…Similar studies of purine nucleotide potencies have been carried out in a number of other tissues and a comparative agonist potency order has been demonstrated (see . In the guinea-pig vas deferens (Fedan et al, 1982;Burnstock et al, 1983;, the rat and guinea-pig urinary bladder (Brown et al, 1979;Burnstock et al, 1983), the perfused pancreas vascular bed (Chapal & Loubatieres-Mariani, 1983), the rat aorta and femoral artery White et al, 1985) and the rabbit ear artery (Kennedy & Burnstock, 1985a), P2-purinoceptors mediate contraction. A rank potency order of a,fi-methylene, 0,ymethylene ATP > ATP = 2-methylthio ATP is indicated in these tissues.…”

Investigation of the preferred Mg(II)‐adenine‐nucleotide complex at the active site of ectonucleotidases in intact vascular cells using phosphorothioate analogues of ADP and ATP

“…Thus the receptor has entirely distinct properties from the ectonucleotidases and probably recognises nucleotide uncomplexed to a metal cation. The magnitude of purinoceptor-induced responses may well be affected, however, by the rate of catabolism exerted by neighbouring ectonucleotidases [19,20] ; thus studies of the type reported here are also important for the rational design of agents that selectively interact with ectonucleotidases or purinoceptors.…”