Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists.
Iminium quaternary protoberberine alkaloids (QPA) have been found to be novel P2X(7) antagonists. To assess their structure-activity relationships, these compounds were modified at their R(1) and R(2) groups and assayed for their ability to inhibit the 2'(3')-O-(4-benzoylbenzoyl)-ATP (BzATP)-induced uptake of fluorescent ethidium by HEK-293 cells stably expressing the human P2X(7) receptor, and their ability to inhibit BzATP-induced IL-1beta release by differentiated THP-1 cells. Compounds 15a and 15d, with alkyl groups at the R(1) position, and especially compound 19h, with the 2-NO(2)-4,5-dimethoxy-benzyl group at the R(2) position, had potent inhibitory efficacy as P2X(7) antagonists.
Lee
Ga Eun
GE
Research Center for Biomolecular Nanotechnology, Department of Life Science, Gwangju Institute of Science and Technology (GIST), 1 Oryong-dong, Buk-gu, Gwangju 500-712, South Korea.
Lee
Ho-Sung
HS
Lee
So Deok
SD
Kim
Jung-Ho
JH
Kim
Won-Ki
WK
Kim
Yong-Chul
YC
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000737:chemistry; D000470:Alkaloids / Q000737:chemistry; D001600:Berberine Alkaloids / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004996:Ethidium / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008956:Models, Chemical; D058919:Purinergic P2 Receptor Antagonists; D011807:Quinolizines / Q000138:chemical synthesis*; D058486:Receptors, Purinergic P2X7; D013329:Structure-Activity Relationship
C539995:5,6-dihydrodibenzo(a,g)quinolizinium; D000470:Alkaloids; D001600:Berberine Alkaloids; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C546468:P2RX7 protein, human; D058919:Purinergic P2 Receptor Antagonists; D011807:Quinolizines; D058486:Receptors, Purinergic P2X7; C009090:protoberberine; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D004996:Ethidium