Cardiovascular Effects of KUR-1246, a New Tetrahydronaphthalen Derivative β2-Adrenoceptor Agonist and a Selective Uterine Relaxant

Abstract

The aim of this study was to assess the cardiovascular effects of KUR-1246 (CAS 194785-31-4, (-)-bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl) phenyl] ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide)monosulfate), a new beta2-adrenoceptor agonist tocolytic agent. In conscious dogs, the intravenous administration of KUR-1246 at 0.1 and 1 microg/kg had no effects on blood pressure, heart rate or femoral artery blood flow. KUR-1246 at 10 and 100 microg/kg significantly decreased blood pressure and increased heart rate. In the electrocardiograms, KUR-1246 did not affect QT intervals or QTc. In addition, the cardiac effects of KUR-1246 were evaluated in in vitro electrophysiological studies. KUR-1246 at 10 micromol/L did not affect action potential parameters (the maximal upstroke velocity, resting membrane potential, action potential amplitude and action potential durations) in isolated papillary muscles of guinea pigs or in the human ether-a-go-go related gene (HERG) tail current recorded from stably transfected human embryonic kidney (HEK) 293 cells. On the basis of these results, the effects of KUR-1246 in conscious dogs on the cardiovascular system appear to be limited to changes in blood pressure and heart rate. Therefore, KUR-1246 is unlikely to provoke ventricular arrhythmias by delaying the ventricular repolarization.

Investigation of β2‐adrenoceptor subtype selectivity and organ specificity for bedoradrine (KUR‐1246), a novel tocolytic beta‐adrenergic receptor stimulant

“…9 It has also been reported in conscious dogs that the intravenous administration of a high concentration of bedoradrine (10 and 100 mg/kg) decreased blood pressure and increased heart rate, but did not affect QT intervals of QTc in an electrocardiogram. 10 In guinea pigs, bedoradrine did not affect the action potential of isolated papillary muscles even at a concentration 1000 times greater than its IC50 value for suppressing spontaneous rat myometrial contractions. 10 In pregnant ewes, although bedoradrine and ritodrine both increased maternal heart rates, the increases in maternal heart rate induced by bedoradrine (17.0~38.8%) were smaller than that induced by ritodrine hydrochloride (59.4~94.1%) at doses that gave an equivalent inhibition of uterine contraction.…”

“…10 In guinea pigs, bedoradrine did not affect the action potential of isolated papillary muscles even at a concentration 1000 times greater than its IC50 value for suppressing spontaneous rat myometrial contractions. 10 In pregnant ewes, although bedoradrine and ritodrine both increased maternal heart rates, the increases in maternal heart rate induced by bedoradrine (17.0~38.8%) were smaller than that induced by ritodrine hydrochloride (59.4~94.1%) at doses that gave an equivalent inhibition of uterine contraction. 16,17 Furthermore, it was reported that the continuous 24-hour infusion of bedoradrine increased maternal heart rate only transiently in pregnant ewes.…”

“…9 Furihata et al further reported that the effects of bedoradrine on the cardiovascular system in conscious dogs appeared to be limited to changes in blood pressure and heart rate and were unlikely to provoke ventricular arrhythmia, which suggests that it has a very weak undesired sideeffect on the cardiovascular system. 10 In a previous in vitro study, we demonstrated that bedoradrine was as efficacious as ritodrine and isoprenaline at inhibiting spontaneous contractions in human pregnant myometrium. 11 Accordingly, we considered that bedoradrine might be a promising tocolytic agent because it may inhibit uterine contraction in women suffering preterm labor without the serious cardiovascular sideeffects induced by b1-AR stimulation.…”