Conformationally rigid dopamine analogues as inhibitors of dopamine and 5-hydroxytryptamine uptake by synaptosomes

Derivatives of trans-decalin with a dopamine moiety incorporated in different conformations were studied as inhibitors of dopamine and 5-HT uptake in rat brain synaptosomes. In three derivatives the relation of the catechol ring and the amino function was gauche, in one isomer it was anti. One of the gauche isomers, (+/-)-2(a)-amino-3(e)-3, 4-dihydroxyphenol-trans-decalin had an affinity to the dopamine uptake system which was about one fourth of that of dopamine itself. The inhibition was competitive. The affinity of other isomers was about ten per cent or less of the affinity of dopamine. The active isomer was identical in conformation to the most active isomer in respective noradrenaline-derivatives tested previously. These results favour the view that the dopamine uptake site is able to accept the substrate as the gauche rotamer. This was not true with 5-HT uptake, and requirements for these two uptake sites may be conformationally different.