Inotropic activity of hydroindene amidinohydrazones.
Several hydroindenic derivatives (7a-methyl-2,3,5,6,7,7a-hexahydro-1H-indenes), bearing an amidinohydrazone at C-5 and different moieties at C-1, have been synthesized and evaluated for their inotropic and chronotropic effects on right- and left-guinea-pig-atria activity. Three of them showed the same profile as digoxin, although with lower potency. The effect on Na(+),K(+)-ATPase (NKA) was also evaluated for these three compounds, observing that two of them, with the same absolute configuration as natural cardenolides, are also NKA inhibitors, while the compound with the opposite configuration lacks such an effect. More interestingly, both active compounds act without affecting the cardiac rhythm. This could be related to the selective inhibition of the human alpha2beta1 isozyme (associated with the inotropic effect) with respect to the alpha1beta1 isozyme (associated with the maintenance of basal ionic levels in the cell and the toxic effect of cardenolides).
Sevillano
Luis G
LG
Facultad de Farmacia, Laboratorio de Química Orgánica y Farmacéutica, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
Melero
Concepción P
CP
Caballero
Esther
E
Tomé
Fernando
F
Lelièvre
Lionel G
LG
Geering
Käthi
K
Crambert
Gilles
G
Carrón
Rosalía
R
Medarde
Manuel
M
San Feliciano
Arturo
A
D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction; D009865:Oocytes / Q000378:metabolism; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis
D000578:Amidines; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D006835:Hydrazones; D007192:Indenes; D007527:Isoenzymes; D000254:Sodium-Potassium-Exchanging ATPase