Harmaline Analogs as Substrate-Selective Cyclooxygenase-2 Inhibitors.

ABSTRACT: We report the design, synthesis, and evaluation of a series of harmaline analogs as selective inhibitors of 2-arachidonylglycerol (2-AG) oxygenation over arachidonic acid (AA) oxygenation by purified cyclooxygenase-2 (COX-2). A fused tricyclic harmaline analog containing a CH₃O substituent at C-6 and a CH₃ group at the C-1 position of 4,9-dihydro-3H-pyrido[3,4-b]indole (compound 3) was the best substrate-selective COX-2 inhibitor of those evaluated, exhibiting a 2AG-selective COX-2 inhibitory IC₅₀ of 0.022 μM as compared to >1 μM for AA. The 2.66 Å resolution crystal complex of COX-2 with compound 3 revealed that this series of tricyclic indoles binds in the cyclooxygenase channel by flipping the side chain of L531 toward the dim

SUBMITTER: Uddin MJ 

PROVIDER: S-EPMC7549255 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature