Rf. Heier et al., SYNTHESIS AND BIOLOGICAL-ACTIVITIES OF -N,N-DIMETHYL-4H-IMIDAZO[4,5,1-IJ]QUINOLIN-5-AMINE AND ITS METABOLITES, Journal of medicinal chemistry, 40(5), 1997, pp. 639-646
The imidazoquinoline (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[(R)-3] is
a potent dopamine agonist when tested in animals but surprisingly sho
ws very low affinity in in vitro binding assays. When incubated with m
ouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethyl
ation and oxidation to ethylamino)-4H-imidazo[4,5,1-ij]quinolin-2(lu)-
one [(R)-6]; intermediate metabolites, where N-demethylation to the im
idazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)
-5 has taken place, are also observed in these incubates. A cross-spec
ies study on the metabolism of (R)-3 in vitro has shown large variatio
ns in the extent of metabolism from species to species. Imidazoquinoli
nones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and
also show good dopaminergic (D2) and serotonergic (5HT(1A)) activitie
s in binding assays. It is probable that these metabolites account at
least in part for the in vivo activity found for (R)-3. Efficient synt
heses for compounds 3-6 as single enantiomers from quinoline are prese
nted together with information on the biological activities and metabo
lic stabilities of these compounds.