Substituted 1,4-benzoxazines bearing an amino side chain at the 2-position were prepared and were found to have a moderate activity on intracellular calcium. Of the compounds studied it was found that those which possess a homoveratrylamino moiety exhibited superior potency. The chain length and the nature of the amine (4-fluorophenylpiperazine, 4-fluorobenzhydryloxyethylamine, N-substituted homoveratrylamine) is discussed. The 4-benzyl-3, 4-dihydro-2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-2H-1, 4-benzoxazine (3c) is the most potent derivative of the series with a ratio of IC50 values against PE (phenylephrine) and K+ of 2.1. Under these test conditions a ratio near 1 indicates potential intracellular calcium activity while a ratio greater than 100 an action on extracellular calcium influx.

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1 The potential use of catecholamines to increase the severity of dysrhythmias evoked by coronary artery ligation in the anaesthetized rat was investigated. Drugs were given intravenously prior to ligation.2 Pressor doses of adrenaline (5 pg/kg) noradrenaline (1 pg/kg) phenylephrine (5-10 pg/kg), and angiotensin (0.25 pg/kg) conferred protection against the development of dysrhythmias. 3 Atropine (1 mg/kg) increased mortality from ventricular fibrilloflutter (VF) and abolished the protective effects of phenylephrine (10 pg/kg).4 Administration of isoprenaline (10pg/kg) significantly increased the incidence of and the mortality from VF. 5 The order of antidysrhythmic drug potency of Org 6001 (1-10 mg/kg), disopyramide (2-10 mg/kg) and practolol (2-10 mg/kg) was similar in both the standard (without isoprenaline) and modified (with isoprenaline) models. 6 Use of the modified method for antidysrhythmic screening purposes allows demonstration of statistically meaningful results with the use of relatively few animals. 7 Comparison of the pattern of VF in the rat heart induced by various means suggests that the diagnosis of ventricular fibrillation can be made with more confidence in the modified method compared to the standard method.