A novel steroid‐like compound F90927 exerting positive‐inotropic effects in cardiac muscle

Abstract

1 Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. 2 F90363 is a racemic mixture composed of the stereoisomers (À)-F90926 and ( þ )-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10 3 times higher than F90927 and most likely resulting from an unspecific interaction. 3 The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L-type Ca 2 þ current I Ca(L) as a main target of F90927, while excluding other components of cardiac Ca 2 þ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. a-and b-adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927. 4 However, vessel contraction and stiffening of the cardiac muscle at high doses (430 mM, 0.36 mg kg À1 , respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.

F90927: A New Member in the Class of Cardioactive Steroids

“…In guinea pigs, treatment with F90927 increased systemic arterial pressure without leading to arrhythmias, even at high concentrations (Pignier et al 2006) (Fig. 4).…”

“…To identify the molecular mechanism underlying the positive inotropy of F90927, electrophysiological experiments were carried out on isolated cardiac myocytes. Whole‐cell voltage‐clamp experiments in combination with laser‐scanning confocal Ca 2+ imaging enabled the identification of the L‐type Ca 2+ channel as the main target and it was shown that F90927 enhances beat‐to‐beat Ca 2+ cycling in myocytes (Pignier et al 2006) (Fig. 2A).…”

“…; * P < 0.05, ** P < 0.01, *** P < 0.001; (A) to (D) versus vehicle, (E) versus zero]. Adapted from (Pignier et al 2006).…”

Design and synthesis of new dihydrotestosterone derivative with positive inotropic activity

“…Additionally, some cardiotonic steroids derivatives have been prepared; for example, the strophanthidin (steroid derivative) increase the force of contraction by changes in the calcium levels in cardiac purkinje fibers [7]. Also, there are studies that show the synthesis of a steroid derivative (F90927) which exerts a positive inotropic activity in cardiac muscle via activation of the L-type calcium channel [8]. Other study indicates that 14b-hydroxyprogesterone increases the contractility of isolated cardiac tissue via glycoside receptor [9].…”

Design and synthesis of new azetidine‐steroid derivative with inotropic activity in a heart failure model

“…[14] Other data showed the total synthesis of a steroid derivative (F90927) which exerted positive inotropic effect on cardiac muscle. [15] Also, the androstane-3, 6,17-trione(E,Z)-3-(2aminoethyl)oxime was prepared via reaction of a ketosteroid with (O-aminoalkyl)hydroxylamine which showed positive inotropic in vitro. [16] In addition, recently a dihydrotestosterone derivative was prepared via reaction of dihydrotestosterone with an oxazin-pyrazol-diamine complex which exert a positive inotropic activity on isolated heart.…”