Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine’s Biological Activity
- 8 January 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (10), 5119-5138
- https://doi.org/10.1021/acs.jmedchem.9b01924
Abstract
Innovative 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 was screened for both agonistic and antagonistic activities against a panel of 168 GPCR drug targets. Although vincamine was without 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.Funding Information
- National Cancer Institute (R01CA172310, R50CA211487)
- American Cancer Society (RSG-18-013-01)
- University of Florida
This publication has 51 references indexed in Scilit:
- A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural productsNature Chemistry, 2013
- The Synthesis of Melohenine B and a Related Natural ProductOrganic Letters, 2012
- Novel opioid cyclic tetrapeptides: Trp isomers of CJ‐15,208 exhibit distinct opioid receptor agonism and short‐acting κ opioid receptor antagonismBritish Journal of Pharmacology, 2012
- Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of actionProceedings of the National Academy of Sciences of the United States of America, 2009
- A semiempirical free energy force field with charge‐based desolvationJournal of Computational Chemistry, 2007
- Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein−Ligand ComplexesJournal of Medicinal Chemistry, 2006
- Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking AccuracyJournal of Medicinal Chemistry, 2004
- Conditioned place preference using opiate and stimulant drugs: A meta-analysisNeuroscience & Biobehavioral Reviews, 1995
- Flow thermolysis rearrangements in the indole alkaloid series: 1,2-dehydroaspidospermidineThe Journal of Organic Chemistry, 1991
- Synthesis of Vinca Alkaloids and Related Compounds XXXV1. Preparation of 1-Ethyl-1-hydroxyethyl-octahydroindolo[2,3-a]quinolizine Derivatives and Reactions of Their Mesylates with Cyanide IonHETEROCYCLES, 1988