Dopaminergic and serotonergic activities of imidazoquinolinones and related compounds.
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.
Department of Medicinal Chemistry, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
M W
MW
Moon
J K
JK
Morris
R F
RF
Heier
C G
CG
Chidester
W E
WE
Hoffmann
M F
MF
Piercey
J S
JS
Althaus
P F
PF
Von Voigtlander
D L
DL
Evans
L M
LM
Figur
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D015259:Dopamine Agents; D015363:Quinolones; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C073698:5-(dipropylamino)-5,6-dihydro-4H-imidazo-(5,1ij)quinolin-2(1H)-one