A new dopaminergic prodrug

Abstract

THE clinical treatment of parkinsonism with the dopamine (DA) precursor L-dopa has certain drawbacks¹ and there are relatively few drugs which directly stimulate DA receptors (although there are many which block them, such as the neuroleptics). There is thus great industrial, academic and clinical interest in the development of new DA-receptor agonists¹. Recently much interest has been given to 2-amino-6, 7-dihydroxytetrahydronaphthalene (ADTN)(Fig. 1), which is known from various in vitro and in vivo studies^2–10 to be a potent, selective and long-acting DA agonist. Two drawbacks to its more widespread study, however, are that the original synthesis was not easy, consisting of eight steps¹¹, and like DA, it does not readily pass the blood–brain barrier, so that it must be administered to animals intraventricularly. Although in vivo ADTN is not the most potent member of its group of 2-aminotetralin derivatives¹², it has the advantage of being structurally very similar to DA, but metabolically more stable. We have developed an improved, simplified synthesis of ADTN consisting of four steps¹³ and we now describe how we have effected the passage of the drug into the brain. In addition to their practical and clinical implications, our results throw new light on the in vivo action of this drug.