A series of 1-amino-3-aryloxy-2-propanols has been synthesized and examined for cardioselective beta-blockade. The introduction of the (3,4-dimethoxyphenethyl)amino group lead to the most cardioselective agents. Structure-activity relationships are discussed. Of the compounds tested 1-[(3,4-dimethoxyphenethyl)amino]-3-(m-tolyloxy)-2-propanol was selected for clinical trial because of optimal potency and selectivity.
Recent studies(l,2) have shown that the nematocyst toxin of Physalia physalis (Portuguese Man-of-war) specifically affects the conduction system in both the neurogenic heart of the land cralb (Cardisoma guanhumi) and the myogenic heart of the rat. In earlier experiments the toxin was dissolved and injected immediately because of its extreme lability. Recently a more stable preparation of the toxin has been made, using a phosphate buffer (pH 6.3) that has prolonged activity sufficiently to allow us to observe the response to gradced doses.The present experiments were designed to study the effects of graded doses of P. physalis toxin upon the canine cardiovascular system, with particular emphasis on the EKG, systemic blood pressure, cardiac output, peripheral vascular resistance, and the levels of serum potassium and sodium. Effects of potassium infusion on toxin-induced arrhythmias were also evaluated.Methods. Toxin was prepared as previously described ( 3 ) , with the exception that the nematocysts were homogenized in 5 ml od isotonic Sorensen's phosphate buffer (containg 18.94 g Na2HP04; 18.16 g KH2P04 ; per liter). Following centrifugation (37,000 X g at 4OC for 30 min) the supernatant solution was lyophilized and stored in the cold in evacuated containers. Just prior to infusion, the lyophilized toxin was dissolved in 5% (w/v) dextrose buffered to pH 6.3 to a final concentration of 40 pg/ml. Eight mongrel dogs, 9.6-11.0 kg, were used in this experiment. The dogs were anesthetized with sodium pentobarbital, 28.6 mg/kg, administered intravenously after a 24-hour fasting period. The left carotid artery was ex-
A series of some 20 novel 2-propanolamines of type I was prepared by reaction of Het-CbLLi with the properly substituted aminoacetonitrile, followed by hydrolysis and reduction. The most potent /3-adrenergic blocking activity was found in the phenanthridine, quinoline, and isoquinoline series, the phenanthridine being almost ten times as active as propranolol. Some ethanolamine homologs of the phenanthridine and quinoline series were prepared for comparison, the former being toxic, the latter somewhat more active than the corresponding 2-propanolamine.
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