EO-199, a demethylated analog of the novel class I antiarrhythmic drug EO-122 was found to antagonize the antiarrhythmic activity of EO-122 and that of procainamide (Class IA). EO-199 did not block significantly the activity of a class IB antiarrhythmic agent, lidocaine. EO-199 also displaced the specific binding of [3H]EO-122 to rat heart membranes similarly to procainamide whereas lidocaine did not. The correlation between binding experiments and pharmacological effects points to a possible subclassification of these drugs; the two chemical analogs EO-199 and EO-122, as well as procainamide (IA) but not lidocaine (IB), compete at the same site or the same state of the sodium channel. The availability of a specific antagonist might be useful for studying the mechanism of action of antiarrhythmic drugs as well as an antidote in cases of antiarrhythmics overdose intoxication.

1989-02-01·Journal of Molecular and Cellular Cardiology2区 · 医学

The specific binding of [3H]EO-122, a radiolabeled class I antiarrhythmic drug to rat heart membranes

2区 · 医学

Article

作者: Oppenheimer, Edna ; Ori, Yaacov ; Meiri, Hamutal

[3H]EO-122, a radiolabeled class I antiarrhythmic drug, has been used to characterize a new specific binding system to rat heart membranes. The binding is saturable and competitive with unlabeled EO-122 and other antiarrhythmic drugs. In this system, [3H]EO-122 binds to two sites. Site A with an apparent Kd of 33.5 +/- 1.5 nM, Bmax of 1.05 +/- 0.15 pmol/mg protein and Hill coefficient nH = 4. Site B with an apparent Kd of 233 +/- 25 nM, Bmax equals 5.7 +/- 0.61 pmol/mg proteins and nH = 6. The binding to site B indicates that this site is pharmacologically relevant to known class IA antiarrhythmic drugs such as quinidine and procainamide. Lidocaine (class IB) does not interact with this site. Interpretation of the high Hill coefficient suggests that the binding of an antiarrhythmic drug to its pharmacologically relevant binding site exposes additional binding sites and/or modulates the affinity of adjacent binding sites.

1989-01-01·Pharmaceutica acta Helvetiae

[Molecular modeling of anti-arrhythmia agents in class Ia and Ib--model conceptions of different binding receptors].

Article

作者: Marrer, S

The molecular properties of quinidine, EO 122, and lidocaine were investigated using theoretical methods (Molecular Modeling). The binding pattern of the molecules were investigated by calculating interaction energies with a negative charged fragment (receptor model). Based on these calculations a model for the differentiation of class Ia and class Ib antiarrhythmic drugs could be deduced. The results explain data which were formulated in the modulated receptor hypothesis. In this way the molecular basis for the preferred affinity of quinidine to the open state of the sodium channel as well as the equal affinity of lidocaine to the open and inactivated state of the channel were defined.

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适应症	最高研发状态	国家/地区	公司	日期
心律失常	临床1期	日本	-	-
心律失常	临床1期	-	Eisai Co., Ltd.	-
心律失常	临床1期	-	Purdue Pharma LP	-
心律失常	临床1期	美国	The Purdue Frederick Co., Inc.	-