Inhibition of catecholamine uptake in the isolated rat heart by haloalkylamines related to phenoxybenzamine

Abstract

1 . Twenty-one haloalkylamine derivatives were tested as inhibitors of both the neuronal uptake of ³H-noradrenaline (NA) by the Uptake₁ mechanism and the extraneuronal uptake of ³H-NA by the Uptake₂ mechanism in the isolated rat heart. 2 . At a concentration of 50 μm most of the compounds tested caused a significant inhibition of both uptake processes, although there were wide differences in the relative effects on Uptake₁ and Uptake₂. Some tentative structure activity relationships for uptake inhibition were formulated from these results. 3 . Phenoxybenzamine was confirmed to be a potent inhibitor of both the Uptake₂ and Uptake₁ mechanisms, with IC50 values for these two systems of 2·8 μm and 0·9 μm respectively. 4 . The substances N-(9-fluorenyl)-N-methyl-β-chloroethylamine (SKF 550), N-(3,4-dimethoxyphenylisopropyl)-N-benzyl-β-chloroethylamine (SKF 625A) and N-(4-methoxyphenoxyisopropyl)-N-benzyl-β-chloroethylamine (SKF 784A) were significantly more potent than phenoxybenzamine as Uptake₂ inhibitors, and were all less potent than phenoxybenzamine as Uptake₁ inhibitors. The compound SKF 550 is the most potent and selective inhibitor of Uptake₂ so far described. It has an IC50 for Uptake₂ of 008 μm, and an IC50 for Uptake₁ of approximately 400 μm. 5 . Comparison of the present results with the known activities of these blocking agents suggests that no correlation exists between adrenoceptor blocking activity and ability of the substances to act as inhibitors of Uptake₂ or Uptake₁.