Activity of NO-releasing impromidine derivatives on histamine H2 and H3-receptors

Molecular hybrids, obtained by coupling the imidazolic portion of impromidine to the nitric oxide (NO)-donor furoxan group, were synthesized. The pharmacological activity of these hybrids at histamine H2 and H3 receptors was tested on the isolated guinea pig papillary muscle and duodenum, respectively, in comparison with corresponding furazan models, devoid of NO-donor properties. In the papillary muscle, both furoxan and the corresponding furazan models showed a positive inotropic effect, prevented by the H2-receptor antagonist famotidine. Compared to impromidine (=0.90, pD2=7.49), the efficacy of these compounds ranged between 0.40 to 0.65 and their potency was 2-3 orders of magnitude lower. Since corresponding furoxan and furazan models gave equivalent effects, mayor influences of NO on the inotropic state of the papillary muscle or on the H2 receptor functions could be excluded. In the duodenum, the furoxan models competitively antagonized the inhibitory effect of the H3 receptor agonist R()methylhistamine on neurogenic cholinergic contractions. pA2 values of furoxan models were equivalent to, or higher than, that of impromidine, but inversely related to their ability to release NO. Accordingly, pre-treatment with the inhibitor of soluble guanylyl cylase, ODQ, enhanced the pA2 value of compound MB-898H (strong NO donor) from 6.86 to 7.66, close to the pA2 value of its furazan analogue MB-914C (7.81). These observations suggest that the furoxan group, similarly to the furazan group, may increase the H3-receptor antagonistic activity of the impromidine structure and that the NO released by furoxan hybrids may affect the interaction of such compounds with the histamine H3 receptor.