Synthesis and histamine H2-receptor activity of heterocyclic impromidine analogues.

Analogues of the H2-agonist impromidine with unsubstituted or substituted aromatic or non-aromatic heterocycles instead of the 5-methylimidazole group were prepared via the benzoylguanidine method and tested for H2-agonistic and H1-antagonistic activity in the guinea-pig isolated right atrium and ileum, respectively. Compounds with unsubstituted 2- or 3-pyridyl, 2-pyrazinyl, or 5-pyrimidyl thioether portion proved to be about equipotent in the atrium (about 2-4x histamine). Highest potency was found in the 5-chloro-3-pyridylthioethylguanidine 8h, that is about 20 times more potent as an H2-agonist than histamine, corresponding to about 8 times the activity of the unsubstituted parent compound 8g. It is demonstrated by the piperidinyl- and morpholinylalkyl guanidines 8m-o that an aromatic ring is not required in the affinity-conferring moiety of H2-agonists (8n: 1.3x histamine). Replacement of the (5-methylimidazol-4-yl)methylthio group in the H2-antagonist cimetidine by halogenated pyridyl, pyrazinyl and pyrimidinyl thioethers resulted in compounds inactive as H2-antagonists, giving further evidence for differences in the structural requirements of the affinity-conferring portions of H2-agonists and antagonists and their mode of interaction with the receptor protein.

Synthesis and histamine H2-agonistic activity of ring-substituted phenyl analogues of impromidine.

Analogues of the H2-agonist impromidine, characterized by a substituted phenyl ring instead of the 5-methyl-4-imidazolyl group, were prepared and tested for their H2-agonistic and H1-antagonistic activity at the guinea-pig atrium and ileum, respectively. The compounds were synthetized via successive aminolysis of diphenyl benzoylcarbonimidate and final acid hydrolysis of the benzoylguanidines. The substituents (mono- or disubstitution with F, Cl, Br, CF3, Me, Et, NO2, NMe2, NEt2, PhCH2) were mainly selected according to the structure-activity relationships known from potent cardiohistaminergics such as arpromidine. While in the arpromidine series substitution of the phenyl ring, in particular halogenation, proved to be very useful for increasing potency, in the series of title compounds, except for the m-fluoro analogue 5g, these variations resulted in a decrease in H2-agonistic activity in the isolated guinea-pig right atrium up to 1.5 orders of magnitude related to the parent compound 5a, which is 10 times more potent than histamine.

[The effect of agonists and antagonists of histamine H1- and H2-receptors on the growth of Mycobacterium tuberculosis H 37 Ra]. / Einfluss von Agonisten und Antagonisten des Histamin-H1- und H2-Rezeptors auf das Wachstum von Mycobacterium tuberculosis H 37 Ra.

The influence of histamine H1- and H2-agonists and -antagonists on the growth of mycobacteria is described. While compounds which are strongly related to histamine improve the growth, predominantly H1-antagonists inhibit bacterial growth.