Cardiotonic agents. 6. Histamine analogues as potential cardiovascular selective H2 agonists.
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.
Lampe
J W
JW
Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.
Hanna
R G
RG
Piscitelli
T A
TA
Chou
Y L
YL
Erhardt
P W
PW
Lumma
W C
WC
Greenberg
S S
SS
Ingebretsen
W R
WR
Marshall
D C
DC
Wiggins
J
J
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*
D002316:Cardiotonic Agents; D011970:Receptors, Histamine H2; D006632:Histamine