ArticleBiochemical pharmacology2010
Identification of a κ-opioid agonist as a potent and selective lead for drug development against human African trypanosomiasis.
Article in Biochemical pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 72 citations in OpenAlex.
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- Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery.Journal of medicinal chemistry · 2025Article
- Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease.Science translational medicine · 2025Article
- Retinoblastoma vulnerability to combinedHeliyon · 2024Article
- Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static-Cidal Screening of Analogues.Journal of medicinal chemistry · 2023Article
- Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis.Journal of medicinal chemistry · 2022Article
- Identification of a Proteasome-Targeting Arylsulfonamide with Potential for the Treatment of Chagas' Disease.Antimicrobial agents and chemotherapy · 2022Article
- DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis.Journal of medicinal chemistry · 2021Article
- Quantitative Structure-Mutation-Activity Relationship Tests (QSMART) model for protein kinase inhibitor response prediction.BMC bioinformatics · 2020Article
- The QACS infectious diseases · 2020Article
- Disruption of Membrane Integrity by the Bacterium-Derived Antifungal Jagaricin.Antimicrobial agents and chemotherapy · 2019Article
- Lead optimization of selective tubulin inhibitors as anti-trypanosomal agents.Bioorganic & medicinal chemistry · 2019Article
- Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions.ChemMedChem · 2018Article
- 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases.European journal of medicinal chemistry · 2018Article
- Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals.Antimicrobial agents and chemotherapy · 2018Article
- Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study.European journal of medicinal chemistry · 2018Article
- Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles.PLoS pathogens · 2018Article
- Molecular characterization of latent GDF8 reveals mechanisms of activation.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Development of a semi-automated image-based high-throughput drug screening system.Frontiers in bioscience (Elite edition) · 2018Article
- Kappa opioid receptors regulate hippocampal synaptic homeostasis and epileptogenesis.Epilepsia · 2018Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
A resazurin-based cell viability assay was developed for phenotypic screening of the LOPAC 1280 'library of pharmacologically active compounds' against bloodstream forms of Trypanosoma brucei in vitro identifying 33 compounds with EC(50) values <1 μM. Counter-screening vs. normal diploid human fibroblasts (MRC5 cells) was used to rank these hits for selectivity, with the most potent (<70 nM) and selective (>700-fold) compounds being suramin and pentamidine. These are well-known antitrypanosomal drugs which demonstrate the robustness of the resazurin cell viability assay. The most selective novel inhibitor was (+)-trans-(1R,2R)-U50,488 having an EC(50) value of 60 nM against T. brucei and 270-fold selectivity over human fibroblasts. Interestingly, (-)-U50,488, a known CNS-active κ-opioid receptor agonist and other structurally related compounds were >70-fold less active or inactive, as were several μ- and κ-opioid antagonists. Although (+)-U50,488 was well tolerated by the oral route and displayed good pharmaceutical properties, including high brain penetration, the compound was not curative in the mouse model of infection. Nonetheless, the divergence of antinociceptive and antitrypanosomal activity represents a promising start point for further exploratory chemistry. Bioinformatic studies did not reveal any obvious candidate opioid receptors and the target of this cytostatic compound is unknown. Among the other potent, but less selective screening hits were compound classes with activity against protein kinases, topoisomerases, tubulin, as well as DNA and energy metabolism.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.