Dopaminergic and serotonergic activities of imidazoquinolinones and related compounds

• Published in: Journal of medicinal chemistry Vol. 35; no. 6; pp. 1076 - 1092
• Main Authors: Moon, Malcolm W, Morris, Jeanette K, Heier, Richard F, Chidester, Connie G, Hoffmann, William E, Piercey, Montford F, Althaus, John S, VonVoigtlander, Philip F, Evans, Dawna L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-03-1992
• Subjects: Aminoquinolines - chemical synthesis; Aminoquinolines - pharmacology; Animals; Binding Sites; Chemistry; Condensed matter: structure, mechanical and thermal properties; Dopamine Agents - chemical synthesis; Dopamine Agents - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Male; Organic chemistry; Organic compounds; Physics; Preparations and properties; Quinolones - chemical synthesis; Quinolones - pharmacology; Rats; Rats, Inbred Strains; Receptors, Dopamine - drug effects; Receptors, Dopamine - metabolism; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; Structure-Activity Relationship; Molecular structure; Angular nitrogen heterocycle; Serotonin agonist; Tricyclic compound; Experimental study; X ray diffraction; Biological activity; Imide; Dopamine agonist; Tertiary amine; Aromatic compound; Heterocyclization; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00084a013

The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.