A Study on the Structure-Activity Relationship of the Cardiotonic Steroids

Imai, Shoichi; Murase, Hiroshi; Kikuchi, Makoto; Okada, Masahiro; Shigei, Tatsuro

doi:10.1254/jjp.15.62

Cited by 17 publications

(7 citation statements)

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“…The importance of a method of this sort in the study of the structure-activity relationship of the compounds was discussed previously (2). A major problem seems to be the diffi culty in obtaining suitable dose-response relationship, due to the slowness of these com pounds in reaching a full effect, little washability, and the involvement of suppressive ef fects on excitation of the muscle cell membrane especially in higher doses.…”

Section: Discussionmentioning

confidence: 99%

“…A series of studies on the structure-activity relationship of cardenolides conducted in this laboratory have brought about much newer knowledge on this problem, including dispensability of 319-hydroxy group or 14β-hydroxy group for cardiotonic ac tion and inactiveness of 15α-hydroxydigitoxigenin (1)(2)(3)(4). In the course of the study, it was felt necessary to describe the potencies of important compounds in terms of numeri cal values.…”

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confidence: 99%

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A New Method for the Biological Assay of Cardiotonic Steroids Based on the Potentiation of Potassium-Contracture of the Frog Ventricular Muscle

1971

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So far there seems to have been no practical method for the assay of cardiotonic ste roids which measures their positive inotropic activity per se directly on the cardiac muscle preparation. A series of studies on the structure-activity relationship of cardenolides conducted in this laboratory have brought about much newer knowledge on this problem, including dispensability of 319-hydroxy group or 14β-hydroxy group for cardiotonic ac tion and inactiveness of 15α-hydroxydigitoxigenin (1-4). In the course of the study, it was felt necessary to describe the potencies of important compounds in terms of numeri cal values. This led us to develop a new assay method which is based on the potentiation of K-contracture of frog ventricular muscle by these compounds, and it has been applied successfully at least to the aglycones. The present paper will report on the new method and the results of the assay of seven aglycones. In addition, the relative potencies of the compounds were compared with those obtained by another method with Straub's isolated frog heart preparation. MATERIALS AND METHODSThe isolated ventricular strip preparation and the isolated heart preparation (Straub's preparation) of the frog (Rana nigroinaculata) were used. Experiments were performed from May through September.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

A New Method for the Biological Assay of Cardiotonic Steroids Based on the Potentiation of Potassium-Contracture of the Frog Ventricular Muscle

1971

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“…Substitution of the acetate residue for resi dues of higher molar volume such as bromoacetate [10], trimethylacetate [14], aminoacetate [ 12],azidoacetate [13] and pyridine ace tate bromide [11], distinctly diminished the potency [7:14:13:12:11:10 = 1.0:0.13:0.11: 0.09: > 0.09 > 0.07]. In most of these glyco sides [10][11][12][13], the potency was lower than that of 16a-gitoxin.…”

Section: Variation In the Genin Moiety (16ct-oh; Tables I Ii)mentioning

confidence: 99%

“…In most of these glyco sides [10][11][12][13], the potency was lower than that of 16a-gitoxin. In the isolated guinea pig heart an increase in potency was also seen after formation of the methyl ether, acetate and nitrate [1:6:7:16 = 1.0:7.1:12.5:25.0], The ex ceptional properties of 16a-gitoxin consisting of weak toxic effects (8,19), were not affected by variations of 16a-OH (tables I, II).…”

Section: Variation In the Genin Moiety (16ct-oh; Tables I Ii)mentioning

confidence: 99%

“…A distinct diminution in efficacy is observed in the case of formation of C-14 andC-15 derivatives (13,17,24,26) while formation of analogous C-16/3-and C-16a-derivatives increases the cardiotonic efficacy depending on the substituent intro duced and on its molar volume (1 ,6 , 9). Repke et al (22) considered similarly long-range di pole-dipole interactions between cardenolides and the receptor enzyme to be important for their cardiotonic activity.…”

Section: Variation In the Genin Moiety (16ct-oh; Tables I Ii)mentioning

confidence: 99%

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Studies on Cardioactive Steroids

Ko¹,

Glusa²

1980

Pharmacology

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The potency of 17 derivatives of 16α-gitoxin was tested in the isolated atrium and heart of the guinea pig and the contractility-increasing activity of the 16α-gitoxin 16α-acetate was compared with that of 16α-gitoxin in the anesthetized dog. The potency of 16α-gitoxin was increased by the substitution of 16α-OH for 16α-methyl ether, 16α-acetate and 16α-nitrate. Substitution of the 16α-acetyl group for substituents with a higher molar volume diminished this enhanced potency. Variation in the digitoxose moiety caused an increase or decrease in potency depending on the position and number of the substituted OH groups. In spite of changes in 16α-OH, the low influence on rhythmicity persisted, as was found in experiments in the dog.

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Alloglaucotoxigenin, Strukturbestimmung Glykoside und Aglykone, 280. Mitteilung

Brandt

Stöcklin

Reichstein

1966

Helvetica Chimica Acta

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Glykoside und Aglykone, 280. MitteiIungZ) von R. Brandt, W. Stocklin und T. Reichstein (16. V. 66) Friihere Befunde. Aus den Samen von Coronilla glauca L. (Fabaceae = Leguminosae-Papilionatae) isolierten STOLL et al. [2] nach Fermentierung ein Furocumarin (= Psoralen) [3] und vier krist. Cardenolide : Alloglaucotoxigenin, Corotoxigenin (11), Coroglaucigenin (111) und Glaucorigenin . Corotoxigenin und Coroglaucigenin wurden seither, teilweise in Form von Glykosiden, auch in verschiedenen anderen Pflanzen aufgefunden [4 bis 121 3), und ihre Struktur ist entsprechend den Formeln I1 und I11 aufgeklart [5] [S]. Glaucorigenin kommt nur in geringen Mengen in den Samen vor, und unseres Wissens ist uber seine Struktur nichts weiteres bekannt. Alloglaucotoxigenin stellt ein Hauptgenin dieser Samen dar und wurde bisher nur in C o r o d l a glauca nachgewiesen [a]. Wir berichten hier uber die Isolierung4) und Struktur dieses Stoffes, die im Einverstandnis mit Herrn Dr. J. RENZ, einem seiner Entdecker, durchgefuhrt wurde. Alloglaucotoxigenin besitzt danach die Formel I V eines 15P-Hydroxycorotoxigenins, was sich aus folgenden Resultaten ergibt. STOLL et al. [Z] haben fur Alloglaucotoxigenin die hypothetische Formel I vorgeschlagen, wobei die Konfiguration am Ring A offen gelassen wurde. Sie berichteten uber folgende Befunde : Die Bruttoformel C23H3206 war durch Analysen gut gesichert. Der Stoff lieferte ein krist. Di-0-acetyl-Derivat C2,HS6O8, aus dem sich mit Hydroxylamin ein krist. Oxim C2,H3,0,N und mit CrO, eine krist. Saure C27H3609 bereiten liessen, wodurch die Anwesenheit einer Aldehydgruppe bewiesen war. Bei der Eehandlung mit HCI-Methanol entstand ein krist. Methyl-cyclohalbacetal C,4H3,06. Ganz gleich verhielt sich Corotoxigenin (11). Diese Reaktion ist, wie wir heute wissen, besonders fur 19-Aldehyde von 3/l-Hydroxy-5ct-steroiden charakteristisch. Die Anwesenheit eines Butenolidringes war auf Grund der positiven LEGL-Reaktion

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A Study on the Structure-Activity Relationship of the Cardiotonic Steroids

Cited by 17 publications

References 5 publications

A New Method for the Biological Assay of Cardiotonic Steroids Based on the Potentiation of Potassium-Contracture of the Frog Ventricular Muscle

A New Method for the Biological Assay of Cardiotonic Steroids Based on the Potentiation of Potassium-Contracture of the Frog Ventricular Muscle

Studies on Cardioactive Steroids

Alloglaucotoxigenin, Strukturbestimmung Glykoside und Aglykone, 280. Mitteilung

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