Studies on the stereoselectivity of the P2‐purinoceptor

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Abstract
ATP, 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. 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. A high degree of stereoselectivity was observed for relaxations of the guinea‐pig taenia coli produced by the P2‐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. 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. The partial stereoselectivity of the P2‐purinoceptor in smooth muscle contrasts with the absolute stereospecificity of P1‐purinoceptors for adenosine on smooth muscle and autonomic nerve terminals and the absolute stereospecificity of the receptor for ADP on the human platelet.