Medicinal chemistry of imidazoquinolinone dopamine receptor agonists.
(R)-5-(Dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]-quinolin-2( 1H)-on e (1a, U-86170), a potent high intrinsic activity dopamine (D2) agonist, has been prepared in eleven steps from quinoline. In several tests, the compound showed dopamine autoreceptor agonist activity at low doses. It showed postsynaptic agonist activity at somewhat higher doses, reversing the effects of reserpine in mice and increasing striatal acetylcholine levels. The compound showed some serotonergic (5HT1A) activity, but was inactive at other receptors. The related monopropylamine 2 (U-91356), also showed good dopaminergic agonist activity, and had improved metabolic stability and oral bioavailability in the rat and monkey when compared to 1a. Compounds 1a and 2 have been prepared in tritiated form, and [3H]1a (69 Ci/mmol) has found use as a D2 agonist radioligand in binding assays. The dopaminergic (D2) and serotonergic (5HT1A) activities of a series of compounds related to 1a have been evaluated using this ligand, [3H]raclopride, and [3H]8-OH DPAT.
Moon
M W
MW
Department of Medicinal Chemistry, Upjohn Laboratories, Upjohn Company, Kalamazoo, MI 49001.
Morris
J K
JK
Heier
R F
RF
Hsi
R S
RS
Manis
M O
MO
Royer
M E
ME
Walters
R R
RR
Lawson
C F
CF
Smith
M W
MW
Lahti
R A
RA
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002417:Cattle; D002626:Chemistry, Pharmaceutical; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000882:Haplorhini; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D014018:Tissue Distribution
D000634:Aminoquinolines; D015259:Dopamine Agents; D007093:Imidazoles; C073698:5-(dipropylamino)-5,6-dihydro-4H-imidazo-(5,1ij)quinolin-2(1H)-one; C083374:5-propylamino-5,6-dihydro-4H-imidazo(4,5,1-ij)quinolin-2(1H)-one