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.
Buschauer
A
A
Institut für Pharmazie, Freien Universität Berlin.
Lachenmayr
F
F
Schunack
W
W
D000818:Animals; D006146:Guanidines / Q000138:chemical synthesis*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis*; D017446:Impromidine; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects*
D006146:Guanidines; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D011970:Receptors, Histamine H2; D006632:Histamine; D017446:Impromidine