Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.
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Heier RF, Dolak LA, Duncan JN, Hyslop DK, Lipton MF, Martin IJ, Mauragis MA, Piercey MF, Nichols NF, Schreur PJ, Smith MW, Moon MW
Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.
J Med Chem. 1997 Feb 28;40(5):639-46.
- PubMed ID
- 9057850 [ View in PubMed]
- Abstract
The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Bromocriptine 5-hydroxytryptamine receptor 1A Ki (nM) 24 N/A N/A Details Bromocriptine Dopamine D2 receptor Ki (nM) 10 N/A N/A Details Bromocriptine Dopamine D3 receptor Ki (nM) 87 N/A N/A Details Lisuride 5-hydroxytryptamine receptor 1A Ki (nM) 0.4 N/A N/A Details Lisuride Dopamine D2 receptor Ki (nM) 0.5 N/A N/A Details Lisuride Dopamine D3 receptor Ki (nM) 1.7 N/A N/A Details Pergolide 5-hydroxytryptamine receptor 1A Ki (nM) 4 N/A N/A Details Pergolide Dopamine D2 receptor Ki (nM) 4 N/A N/A Details Pergolide Dopamine D3 receptor Ki (nM) 4 N/A N/A Details Ropinirole Dopamine D2 receptor Ki (nM) 7.2 N/A N/A Details Ropinirole Dopamine D3 receptor Ki (nM) 19 N/A N/A Details