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-chloroethylamin (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 0·08 μM, and an IC50 for Uptake1 of approximately 40·0 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.
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Selected References
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- IVERSEN L. L. THE UPTAKE OF NORADRENALINE BY THE ISOLATED PERFUSED RAT HEART. Br J Pharmacol Chemother. 1963 Dec;21:523–537. doi: 10.1111/j.1476-5381.1963.tb02020.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iversen L. L., Langer S. Z. Effects of phenoxybenzamine on the uptake and metabolism of noradrenaline in the rat heart and vas deferens. Br J Pharmacol. 1969 Nov;37(3):627–637. doi: 10.1111/j.1476-5381.1969.tb08501.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iversen L. L. Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmacol. 1971 Apr;41(4):571–591. doi: 10.1111/j.1476-5381.1971.tb07066.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iversen L. L., Salt P. J. Inhibition of catecholamine Uptake-2 by steroids in the isolated rat heart. Br J Pharmacol. 1970 Nov;40(3):528–530. doi: 10.1111/j.1476-5381.1970.tb10637.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kalsner S., Nickerson M. Effects of a haloalkylamine on responses to and disposition of sympathomimetic amines. Br J Pharmacol. 1969 Mar;35(3):440–455. doi: 10.1111/j.1476-5381.1969.tb08285.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lightman S. L., Iversen L. L. The role of uptake2 in the extraneuronal metabolism of catecholamines in the isolated rat heart. Br J Pharmacol. 1969 Nov;37(3):638–649. doi: 10.1111/j.1476-5381.1969.tb08502.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MORGAN H. E., HENDERSON M. J., REGEN D. M., PARK C. R. Regulation of glucose uptake in muscle. I. The effects of insulin and anoxia on glucose transport and phosphorylation in the isolated, perfused heart of normal rats. J Biol Chem. 1961 Feb;236:253–261. [PubMed] [Google Scholar]
- NICKERSON M., NOMAGUCHI G. M. Adrenergic blocking action of phenoxy-ethyl analogues of dibenamine. J Pharmacol Exp Ther. 1951 May;102(1):379–396. [PubMed] [Google Scholar]