jm9b01924_si_001.pdf (23.24 MB)
Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine’s Biological Activity
journal contribution
posted on 2020-03-20, 19:41 authored by Verrill
M. Norwood, Ariana C. Brice-Tutt, Shainnel O. Eans, Heather M. Stacy, Guqin Shi, Ranjala Ratnayake, James R. Rocca, Khalil A. Abboud, Chenglong Li, Hendrik Luesch, Jay P. McLaughlin, Robert W. HuigensInnovative
discovery strategies are essential to address the ongoing
opioid epidemic in the United States. Misuse of prescription and illegal
opioids (e.g., morphine, heroin) has led to major problems with addiction
and overdose. We used vincamine, an indole alkaloid, as a synthetic
starting point for dramatic structural alterations of its complex,
fused ring system to synthesize 80 diverse compounds with intricate
molecular architectures. A select series of vincamine-derived compounds
were screened for both agonistic and antagonistic activities against
a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although
vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against
hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned
place preference (CPP) and stress-induced reinstatement of extinguished
morphine-CPP in mouse models of opioid reward and relapse. These results
demonstrate that the ring distortion of vincamine offers a promising
way to explore new chemical space of relevance to opioid addiction.