Studies on cardiac ingredients of plants. XIII: Chemical modification of gitoxin to cardiotonic compounds without vascular effect.
Nitrated gitoxins (4) and bufotoxin homologues with various lengths of alkyl chain at C-3 of the steroid nucleus (10) were prepared from gitoxin (1). The pharmacological activities of the resulting compounds (4 and 10) were evaluated by measurement of inhibitory effect on NA+, K(+)-adenosine triphosphatase (ATPase) prepared from dog kidney, positive inotropic effect (PIE) on isolated guinea-pig papillary muscle preparations, and the effect on smooth muscle using the mesenteric artery from spontaneously hypertensive rats. Most of the compounds showed a smaller contractile effect on the arterial muscle. Among these compounds, gitoxin 3"-nitrate (4g) exhibited the most desirable biological activities, such as PIE comparable to that of 1, 1.25 times wider concentration-dependent range than 1, and lack of contractile activity on vascular muscle.
Nagatsu
A
A
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Nakamura
Y
Y
Takemoto
K
K
Shibatomi
K
K
Nagai
S
S
Ueda
T
T
Sakakibara
J
J
Hidaka
H
H
Fujita
M
M
Hotta
Y
Y
Takeya
K
K
Asano
M
M
Hashimoto
T
T
Asakawa
Y
Y
D000818:Animals; D002018:Bufanolides / Q000737:chemistry / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000494:pharmacology; D004077:Digoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D007668:Kidney / Q000201:enzymology; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010946:Plants, Medicinal / Q000737:chemistry*; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
D002018:Bufanolides; D002316:Cardiotonic Agents; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase; C026738:bufotoxin; C005003:gitoxin