Inhibition of neurotransmitter release from enteric nerve endings by 2-[p-(carboxyethyl)-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 of enteric nerves. In characterizing these receptors, the response of the electrically stimulated guinea pig ileum longitudinal muscle-myenteric plexus preparation to receptor-selective analogs of adenosine was investigated and the antagonism of such activity by selective antagonists quantitated. The A1-selective agonist N6-cyclopentyladenosine, the nonselective agonist 5'-N-ethylcarboxamidoadenosine and the 2-substituted uronamides, 2-[p-(carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine and 2-[-(4-fluorophenyl)-ethoxy]-5'-N-ethylcarboxamidoadenosine, both relatively A2-selective agonists, inhibited field-stimulated responses of the ileum with the potency rank order: N6-cyclopentyladenosine > 5'-N-ethylcarboxamidoadenosine >> 2-[p-(carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine approximately 2-[-(4-fluorophenyl)-ethoxy]-5'-N-ethylcarboxamidoadenosine. Antagonism of these responses by receptor-selective antagonists was quantitated using the Schild technique and, for 1,3-dipropyl-8-cyclopentylxanthine, the A1-selective antagonist, demonstrated simple competitive interaction with the responses to N6-cyclopentyladenosine yielding a linear Schild isobole with unit slope. In contrast, responses to the uronamides could not be antagonized in a simple competitive manner. The potency order of the selective agonists is compatible with the presence on enteric nerve endings of an A1 receptor but does not support the presence of the A2 subtype. Moreover, these data demonstrate that the putatively A2-selective adenosine analogs 2-[p-(carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine and 2-[-(4-fluorophenyl)-ethoxy]-5'-N-ethylcarboxamidoadenosine interact with 1,3-dipropyl-8-cyclopentylxanthine at enteric nerve adenosine receptors in a manner which is not compatible with simple competitive interactions.(ABSTRACT TRUNCATED AT 250 WORDS)