title: Synthesis and structure-activity relationships of novel, substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ga Eun
authors.initials: GE
authors.lastname: Lee
authors.forename: Ho-Sung
authors.initials: HS
authors.lastname: Lee
authors.forename: So Deok
authors.initials: SD
authors.lastname: Lee
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: 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
chemical_list: 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