title: Cardiotonic agents. 6. Histamine analogues as potential cardiovascular selective H2 agonists.
abstract: Twenty-six alkyl and aralkyl histamine analogues were prepared as potential cardiotonic agents. Compounds were designed to allow interaction with a putative secondary aryl binding site at the H2 receptor, the presence of which was inferred from the structure of cyprohepatadine, which is known to have H2-antagonist properties. The compounds were examined for inotropic activity in ferret papillary muscle. Potent inotropic activity was generally found in N-alkyl- and N,N-dialkylimidazole-4-ethanamines, whereas N-(amidoalkyl)imidazole-4-ethanamines and N-alkylimidazole-4-propanamines were at best weakly active. Five compounds were examined in screens designed to assess hemodynamic effects and gastric acid secretion in vivo. Two of these compounds, alpha-(3-phenyl-2-transpropenyl)-1H-imidazole-4-ethanamine and N-heptyl-1H-imidazole-4-ethanamine, showed positive inotropic activity with minimal effects on heart rate and mean arterial pressure in vivo; however, both compounds were found to stimulate gastric acid secretion. These results demonstrate that selectivity between various H2-receptor-mediated activities can be obtained with substituted histamine analogues.
authors.affiliation: Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.
authors.forename: J W
authors.initials: JW
authors.lastname: Lampe
authors.forename: R G
authors.initials: RG
authors.lastname: Hanna
authors.forename: T A
authors.initials: TA
authors.lastname: Piscitelli
authors.forename: Y L
authors.initials: YL
authors.lastname: Chou
authors.forename: P W
authors.initials: PW
authors.lastname: Erhardt
authors.forename: W C
authors.initials: WC
authors.lastname: Lumma
authors.forename: S S
authors.initials: SS
authors.lastname: Greenberg
authors.forename: W R
authors.initials: WR
authors.lastname: Ingebretsen
authors.forename: D C
authors.initials: DC
authors.lastname: Marshall
authors.forename: J
authors.initials: J
authors.lastname: Wiggins
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D005289:Ferrets; D005744:Gastric Acid / Q000378:metabolism*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000031:analogs & derivatives*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D011970:Receptors, Histamine H2 / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D011970:Receptors, Histamine H2; D006632:Histamine