THIOL GROUP MAY BE INVOLVED IN THE IRREVERSIBLE BLOCKADE OF PRESYNAPTIC 2-ADRENORECEPTORS BY PYREXTRAMINE AND BENEXTRAMINE IN THE ISOLATED GUINEA PIG ILEUM

This study, conducted on isolated guìnea pig ileum, was designed to establish the mechanism of presynaptic 2-adrenoreceptor blockade by the tetramine disulfides, benextramine and pyrextramine. At 1 M these drugs irreversibly blocked norepìnephrine (NE)-induced inhibition of the twitch response to electrical stimulation. This may be the result of covalent bond formation between the disulfide bridge of the inhibitor and a thiol function at the receptor level through an interchange reaction since the benextramine carbon analogue did not affect NE response under the same conditions. Furthermore, NE (10 uM) failed to protect presynaptic 2-adrenoreceptors from pyrextramine blockade whereas idazoxan (0.1 M) completely abolished the irreversible antagonism of pyrextramine (l uM). Thjs finding suggests that the tetramine disulfide binding site may coincide with that of idazoxan and is different from the NE binding site.