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.