INHIBITION OF NEUROTRANSMITTER RELEASE FROM ENTERIC NERVE-ENDINGS BY L)-PHENETHYLAMINO]-5'-N-ETHYLCARBOXAMIDO-ADENOSINE (CGS-21680) AND RELATED ADENOSINE-ANALOGS - LACK OF SIMPLE COMPETITION BY ANTAGONISTS

Adenosine receptors on enteric nerves mediate inhibitory responses to adenosine and its analogs and contribute to the overall excitability o f enteric nerves. In characterizing these receptors, the response of t he electrically stimulated guinea pig ileum longitudinal muscle-myente ric plexus preparation to receptor-selective analogs of adenosine was investigated and the antagonism of such activity by selective antagoni sts quantitated. The A1-selective agonist N6-cyclopentyladenosine, the nonselective agonist 5'-N-ethylcarboxamidoadenosine and the 2-substit uted uronamides, yl)-phenethylaminol-5'-N-ethylcarboxamidoadenosine an d orophenyl)-ethoxy]-5'-N-ethylcarboxamidoadenosine, both relatively A 2-selective agonists, inhibited field-stimulated responses of the ileu m with the potency rank order: N6-cyclopentyladenosine > 5'-N-ethylcar boxamidoadenosine much greater than yl)-phenethylamino]-5'-N-ethylcarb oxamidoadenosine almost-equal-to orophenyl)-ethoxy]-5'-N-ethylcarboxam idoadenosine. Antagonism of these responses by receptor-selective anta gonists was quantitated using the Schild technique and, for 1,3-diprop yl-8-cyclopentylxanthine, the A1-selective antagonist, demonstrated si mple competitive interaction with the responses to N-cyclopentyladenos ine yielding a linear Schild isobole with unit slope. In contrast, res ponses to the uronamides could not be antagonized in a simple competit ive manner. The potency order of the selective agonists is compatible with the presence on enteric nerve endings of an Al receptor but does not support the presence of the A2 subtype. Moreover, these data demon strate that the putatively A2-selective adenosine analogs yl)-phenethy lamino]-5'-N-ethylcarboxamidoadenosine and uorophenyl)-ethoxy]-5'-N-et hylcarboxamidoadenosine interact with 1,3-dipropyl-8-cyclopentylxanthi ne at enteric nerve adenosine receptors in a manner which is not compa tible with simple competitive interactions. These studies demonstrate that analogs of adenosine possessing the 5'-uronamide substituent beha ve as full agonists at the enteric neural adenosine A1 receptor but su ggest that they act in a distinct way compared to the nonuronamide A1- selective agonists.