Occurrence and pharmacological significance of metabolic ortho-hydroxylation of 5- and 8-hydroxy-2-(di-n-propylamino)tetralin.

Aromatic ortho-hydroxylation in the liver might be one of several possible reasons for the low bioavailabilities of the potent, centrally acting dopaminergic and serotoninergic agonists 5- and 8-hydroxy-2-(di-n-propylamino)tetralin, respectively. In vitro and in vivo experiments showed that such an oxidative metabolism did indeed take place. However, the amount of hydroxylated metabolites found in the brain was estimated to represent only 0.3% of the total amount of drug administered. The O-methylation rates of these catechols were also measured in vitro and showed that 5,6-dihydroxy-2-(di-n-propylamino)tetralin is a poor substrate for catechol O-methyltransferase (COMT) and that its 7,8-dihydroxy isomer is virtually devoid of substrate activity. No O-methylated metabolites were detected in the in vivo samples analyzed. A new synthetic strategy was applied to achieve the isomeric catechols studied. 5-Methoxy- or 8-methoxy-2-(di-n-propylamino)tetralin was lithiated in the ortho position and the metalated species was subsequently quenched in nitrobenzene, yielding the methoxy hydroxy isomers, which were heated in 48% aqueous HBr to achieve the corresponding catechols.