Inhibition of Catecholamine Uptake in the Isolated Rat Heart by Haloalkylamines Related to Phenoxybenzamine

1. Twenty-one haloalkylamine derivatives were tested as inhibitors of both the neuronal uptake of (3)H-noradrenaline (NA) by the Uptake(1) mechanism and the extraneuronal uptake of (3)H-NA by the Uptake(2) mechanism in the isolated rat heart.2. At a concentration of 50 muM most of the compounds tested caused a significant inhibition of both uptake processes, although there were wide differences in the relative effects on Uptake(1) and Uptake(2). 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 Uptake(2) and Uptake(1) mechanisms, with IC50 values for these two systems of 2.8 muM and 0.9 muM respectively.4. The substances N-(9-fluorenyl)-N-methyl-beta-chloroethylamine (SKF 550), N-(3,4-dimethoxyphenylisopropyl)-N-benzyl-beta-chloroethylamin (SKF 625A) and N-(4-methoxyphenoxyisopropyl)-N-benzyl-beta-chloroethylamine (SKF 784A) were significantly more potent than phenoxybenzamine as Uptake(2) inhibitors, and were all less potent than phenoxybenzamine as Uptake(1) inhibitors. The compound SKF 550 is the most potent and selective inhibitor of Uptake(2) so far described. It has an IC50 for Uptake(2) of 0.08 muM, and an IC50 for Uptake(1) of approximately 40.0 muM.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 Uptake(2) or Uptake(1).