Summary
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1.
The dissociation constants (pKa1, pKa2, pKCOOH), n-octanol/water distribution coefficients D (at pH 7.4) and partition coefficients P of a series of sympathomimetic amines and of catecholamines, their precursors and metabolites were determined.
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2.
The influence of different substituents of compounds bearing an amino group on lipophilicity (log D and log P) and on pKa1 values was estimated. Introduction of a hydroxyl group reduced the lipophilicity of phenylethylamines and related compounds. Hydroxylation of the phenyl ring led to a stronger reduction of lipophilicity than did β-hydroxylation. An additional methoxy group in the molecule reduced the lipophilicity to only a very small degree. Alkylation always increased lipophilicity; the degree was dependent on the position and on the size of the alkyl group. The pKa1 values of phenolic amines were more influenced by the introduction of hydrophilic groups than by lipophilic groups. Hydroxylation always decreased the pKa1 values independent of the position of the hydroxyl group, while the introduction of a methyl group at the N-terminal of phenolic amines increased it. An α-methyl group or a methoxy group at the phenyl ring was without any effect on pKa1 values.
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3.
For noradrenaline and its precursors the following rank order of lipophilicity was observed (at pH 7.4): tyrosine > dopa > dopamine > noradrenaline; the rank order for the metabolites of noradrenaline was MOPEG > DOPEG > normetanephrine > VMA > DOMA.
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4.
The lipophilicity (at pH 7.4) of the metabolites of noradrenaline was correlated with the rate constants for efflux of these metabolites from peripheral organs (Graefe, 1976; Henseling et al., 1978; Fiebig and Trendelenburg, 1978a).
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This study was supported by the Deutsche Forschungs-gemeinschaft (Bo 521/2); some of the present results have been reported to the German Pharmacological Society (Bönisch and Mack, 1978)
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Mack, F., Bönisch, H. Dissociation constants and lipophilicity of catecholamines and related compounds. Naunyn-Schmiedeberg's Arch. Pharmacol. 310, 1–9 (1979). https://doi.org/10.1007/BF00499868
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DOI: https://doi.org/10.1007/BF00499868