Synthesis and pharmacological characterisation of a series of compounds obtained by joining, through appropriate spacers, NO-donor furoxan and nitrooxy moieties to the imidazole ring, as well as their structurally related analogues devoid of NO-donating properties are described. All the products were studied for their capacity to interact with H3-receptors present on the guinea-pig ileum and with H2-receptors present on guinea-pig right atrium. The whole series of products displayed reversible H3-antagonistic activity. No activity on H2-receptors was observed when the products were tested at 10 μM concentration. Many of the products were also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of their H3-antagonism. This phenomenon seems to be dependent on various factors; for some compounds it proved to be dependent on NO-mediated sGC activation, for other products it could be due to their weak M3-antagonism. The investigation of the lipophilic-hydrophilic balance of all the products indicates, for many of them, an ideal value to cross the blood-brain barrier.
A new class of NO-donor H3-Antagonists
TOSCO, Paolo;BERTINARIA, Massimo;DI STILO, Antonella;MARINI, Elisabetta;ROLANDO, Barbara;SORBA, Giovanni;FRUTTERO, Roberta;GASCO, Alberto
2004-01-01
Abstract
Synthesis and pharmacological characterisation of a series of compounds obtained by joining, through appropriate spacers, NO-donor furoxan and nitrooxy moieties to the imidazole ring, as well as their structurally related analogues devoid of NO-donating properties are described. All the products were studied for their capacity to interact with H3-receptors present on the guinea-pig ileum and with H2-receptors present on guinea-pig right atrium. The whole series of products displayed reversible H3-antagonistic activity. No activity on H2-receptors was observed when the products were tested at 10 μM concentration. Many of the products were also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of their H3-antagonism. This phenomenon seems to be dependent on various factors; for some compounds it proved to be dependent on NO-mediated sGC activation, for other products it could be due to their weak M3-antagonism. The investigation of the lipophilic-hydrophilic balance of all the products indicates, for many of them, an ideal value to cross the blood-brain barrier.
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