The metabolism of dopamine, NN-dialkylated dopamines and derivatives of the dopamine agonist 2-amino-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) by catechol-O-methyltransferase

A variety of dopamine derivatives and analogues were investigated to assess their potential to act as catechol-O-methyltransferase (COMT) substrates using purified, homogeneous pig liver enzyme. This enabled accurate kinetic constants to be determined as opposed to previous in-vivo studies (Rollema et al 1980; Horn et al 1981; Costall et al 1982; Feenstra et al 1983). 2-Amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN) proved to be a far better substrate (Km = 0.082 mM; Vmax = 300 mu mg-1 protein) than its 5,6-dihydroxy isomer (Km = 2.60 mM; Vmax = 113.9 mu mg-1 protein). This result supports evidence suggesting that differences in brain concentration of these isomers are due to their differential susceptibility to O-methylation by COMT (Rollema et al 1980). A similar result was obtained with a series of NN-di-n-alkyl substituted ADTN derivatives: the same pattern of preferential O-methylation of A-6,7-DTN derivatives over the corresponding A-5,6-DTN isomers was observed. However, increasing the length of the alkyl chain increased the susceptibility of both isomers to metabolism by COMT as shown by a decline in Km. An homologous series of NN-di-n-alkylated dopamines showed a similar trend implying that more hydrophobic compounds are better COMT substrates