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

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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.