The Effect of Deuterium Labelling on Ionization Constants and Lipophilicity of Trace Amines

Abstract

In recent work in this laboratory it was observed that when equimolar mixtures of phenylethylamine (PE) and α,α,β,β-tetradeutero phenyl ethyl ami ne (PE-d₄) were injected intraperitoneally into the rat, the amount of PE-d₄ in the rat brain greatly exceeded that of PE (Dyck et al.). This could be explained by the resistance of PE-d₄ to oxidation by MAO or perhaps a higher transport rate of PE-d₄ into the brain. The transport of an amine across membrane barriers may be approximately related to its distribution coefficient (D) into a lipophilic solvent such as an 1-octanol system (Leo et al., 1971). The distribution coefficient is in turn related to the partition coefficient (P), the dissociation constant (PK_a) and the of the aqueous solution (Mack and Bonisch, 1979). Labelling of the alkyl chain of alkyl amines and acids tends to increase the PK_a value (Halevi et al., 1963; Vree et al., 1971). This in turn, assuming constant partition coefficient, would reduce the distribution coefficient and hence the relative transport of a deuterium labelled trace amine into the lipophilic solvent.