Dissociation constants and lipophilicity of catecholamines and related compounds

Summary

• 1. The dissociation constants (pK_a1, pK_a2, pK_COOH), 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.

• 2. The influence of different substituents of compounds bearing an amino group on lipophilicity (log D and log P) and on pK_a1 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 pK_a1 values of phenolic amines were more influenced by the introduction of hydrophilic groups than by lipophilic groups. Hydroxylation always decreased the pK_a1 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 pK_a1 values.

• 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.

• 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).