Synthesis and SAR studies of 2-oxoquinoline derivatives as CB2 receptor inverse agonists.
The highly CB2 selective cannabinoid receptor inverse agonist, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid N-benzo[1,3]dioxol-5-ylmethyl)amide (JTE-907; 9b), served as the lead compound for investigating the structure-activity relationships of its analogues and in the search for more potent and effective CB2 receptor inverse agonists. A series of aromatic amides of 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid 6 was synthesized, and the CB2 receptor activities of the compounds were determined by a [35S]GTPgammaS-binding assay using membranes of CHO cells stably transfected with the human CB2 receptor. As a result, all the compounds were defined as full CB2 receptor inverse agonists, and additionally, except for two 3,4-dihydroxyphenylalkylamides, they were found to be equally potent as SR144528.
Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland. Katri.Raitio@uku.fi
Katri H
KH
Raitio
Juha R
JR
Savinainen
Jouko
J
Vepsäläinen
Jarmo T
JT
Laitinen
Antti
A
Poso
Tomi
T
Järvinen
Tapio
T
Nevalainen
D000818:Animals; D016466:CHO Cells; D001892:Camphanes / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001892:Camphanes; D004149:Dioxoles; C422645:JTE 907; D011720:Pyrazoles; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528