6v3r

Publication Abstract from PubMed

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 muM as compared to >1 muM for AA. The 2.66 A 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 dimer interface. This novel tricyclic indole series provides the foundation for the development of promising substrate-selective molecules capable of increasing endocannabinoid (EC) levels in the brain to offer new treatments for a variety of diseases, from pain and inflammation to stress and anxiety disorders.

Harmaline Analogs as Substrate-Selective Cyclooxygenase-2 Inhibitors.,Uddin MJ, Xu S, Crews BC, Aleem AM, Ghebreselasie K, Banerjee S, Marnett LJ ACS Med Chem Lett. 2020 Feb 14;11(10):1881-1885. doi:, 10.1021/acsmedchemlett.9b00555. eCollection 2020 Oct 8. PMID:33062168^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.