A mild cross-coupling reaction to access several N-alkenyl-substituted indoles has been developed. The coupling procedure involves treating a NH-indole with various alkenyl bromides using a combination of 10 mol % of copper(I) iodide and 20 mol % of ethylenediamine as the catalyst in dioxane at 110 °C in the presence of K(3)PO(4) as the base. When treated with acid, these unique enamines produce a dimeric product derived from a preferred protonation reaction at the enamine π-bond. A cationic cyclization reaction of the readily available 2-(2-(1H-indol-1-yl)allyl)cyclopentanol was utilized to construct tetracyclic indole derivatives with a quaternary stereocenter attached to the C(2)-position of the indole ring. An alternative strategy for selective functionalization at the C(2)-position of a N-alkenyl-substituted indole derivative that was also studied involves a radical cyclization of a xanthate derivative. The work described provides an attractive route to the tetracyclic core of some vinca alkaloids, including the tetrahydroisoquinocarbazole RS-2135.

1996-03-01·Journal of Cardiovascular Pharmacology4区 · 医学

Possible Involvement of Altered Na+-Ca2+ Exchange in Negative Inotropic Effects of Class I Antiarrhythmic Drugs on Rabbit and Rat Ventricles

4区 · 医学

Article

作者: Ito, Katsuaki ; Koike, Hiroyuki ; Nagafuchi, Kazunori ; Yorikane, Ryosuke ; Taga, Atsuo

We investigated the way in which Na+ channel blocking class I antiarrhythmic drugs, lidocaine (30 mu M), flecainide (30 mu M), and RS-2135 (100 mu M) affected contractions elicited by several protocols in rat and rabbit ventricular strips. Rabbit ventricles showed a positive force-frequency relation, and antiarrhythmic drugs inhibited the contraction, flattening the force-frequency curve. In contrast, rat ventricles showed a negative force-frequency relation, and the drugs shifted the force-frequency curve downward. Rapid-cooling contracture (RCC) also showed a positive or negative dependence on the frequency of preceding stimulation in rabbit or rat ventricles, respectively. All drugs inhibited the RCC, suggesting that they reduced the Ca2+ content in the sarcoplasmic reticulum. Ryanodine (1 mu M) abolished the RCC in both muscles and the contraction in rat muscles, but partially decreased contractions at high frequencies in rabbit ventricles. Antiarrhythmic drugs caused a further inhibition of contractions in the presence of ryanodine in rabbit ventricles. These results indicate that inhibition of Na+ channels by antiarrhythmic drugs alters Na+ -Ca2+ exchange, resulting in a decrease in the Ca2+ content in the sarcoplasmic reticulum (SR) and the Ca2+ entry through the exchanger.

1994-07-01·Journal of Cardiovascular Pharmacology4区 · 医学

Effects of RS-2135, a Novel Class I Antiarrhythmic Agent, on Sustained Ventricular Tachycardia After Coronary Embolization in Conscious Dogs

4区 · 医学

Article

作者: Miyake, Shigeki ; Koike, Hiroyuki ; Mizuno, Hiroshi ; Yorikane, Ryosuke ; Itoh, Yuko

To assess the ability of RS-2135, a novel class I antiarrhythmic agent to suppress ischemia-induced ventricular arrhythmias, we produced myocardial infarction (MI) by introducing a glass bead into the coronary artery of the dog (bead model). Ventricular arrhythmias after coronary embolization were as severe and long-lasting as those that occur after two-stage coronary artery ligation as described by Harris. RS-2135 (1.25 and 2.5 mg/kg intravenously, i.v.) suppressed sustained ventricular tachycardia (SVT) 24 h after coronary embolization in the bead model. The antiarrhythmic effects of i.v. administration of RS-2135 were more potent and more long-lasting than those of lidocaine (5 and 10 mg/kg i.v.), mexiletine (5 and 10 mg/kg i.v.), disopyramide (2.5 and 5 mg/kg i.v.), and flecainide (2.5 and 5 mg/kg i.v.). The antiarrhythmic effects of oral (p.o.) administration of RS-2135 were evaluated 48 h after coronary embolization. RS-2135 (10 mg/kg p.o.) was equipotent to flecainide (10 mg/kg p.o.) and twice as potent as disopyramide (20 mg/kg p.o.) and mexiletine (20 mg/kg p.o.). Onset of antiarrhythmic effects after p.o. RS-2135 was slower than that of other drugs. These data suggest that the bead model is as useful as the Harris model for evaluation of the antiarrhythmic potential of chemicals and that RS-2135, either i.v. or p.o., is effective against SVT after acute MI.

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