N-methyl,N-propargyl-2-aminotetralins:novel dopamine agonists with monoamine oxidase inhibiting properties.
A series of mono- (5 and 7) and dihydroxylated (5,6 and 6,7)N-methyl,N-propargyl-2-aminotetralins were studied with respect to their dopamine agonistic and monoamine oxidase inhibitory activities. MAO inhibition was found to be reduced by hydroxylation of the aromatic ring. Among the hydroxylated compounds the 7-OH analogue was the most potent inhibitor in in vitro and ex vivo experiments. Both catecholic structures were equipotent with apomorphine as displacers of the specific in vitro binding of [3H]NPA to rat striatal homogenates. Moreover, the catecholic analogues had a potency comparable to that of apomorphine in the gamma-butyrolactone model whereas the monohydroxy analogues were less active. On the basis of their effectiveness to induce stereotypy in rats and to reverse reserpine-induced hypomotility in mice (both used as indices of postsynaptic dopamine receptor stimulation) the catecholic compounds were more potent than the monohydroxy analogues but much less active than apomorphine. Dopamine agonistic activity was also reflected in decreased HVA levels in the striatum whilst effects on striatal 3-MT levels reflected the balance between dopamine agonistic (decrease in 3-MT) and MAO inhibitory (increase in 3-MT) activity of the various compounds. It was concluded that both the mono- and dihydroxylated compounds have MAO inhibiting and dopamine agonistic activities. The MAO inhibitory activity predominated within the monohydroxy structures whereas the dopamine agonistic effect was predominant for the catecholic compounds. It would thus appear that, at least for the 2-aminotetralins, it is difficult to prepare an analogue which combines a high degree of both MAO inhibitory and DA agonistic activity.
D015107:4-Butyrolactone / Q000494:pharmacology; D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000201:enzymology; D003342:Corpus Striatum / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D012110:Reserpine / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000480:Alkynes; D008996:Monoamine Oxidase Inhibitors; D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C009074:N-n-propylnorapomorphine; D004295:Dihydroxyphenylalanine; D012110:Reserpine; D001058:Apomorphine; D015107:4-Butyrolactone; D004298:Dopamine