Harmaline Analogs as Substrate-Selective Cyclooxygenase-2 Inhibitors.

Publication Type:

Journal Article


ACS Med Chem Lett, Volume 11, Issue 10, p.1881-1885 (2020)


<p>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 CHO substituent at C-6 and a CH group at the C-1 position of 4,9-dihydro-3-pyrido[3,4-]indole (compound ) was the best substrate-selective COX-2 inhibitor of those evaluated, exhibiting a 2AG-selective COX-2 inhibitory IC of 0.022 μM as compared to &gt;1 μM for AA. The 2.66 Å resolution crystal complex of COX-2 with compound 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.</p>