The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2
Open accessAbstract
Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [(35)S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.
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Cites
Benchmarking sets for molecular docking.
Huang, N., Shoichet, B. K., & Irwin, J. J. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm0608356 · Cited by 1,318
Automated design of ligands to polypharmacological profiles
Besnard, J., Ruda, G. F., Setola, V., Abecassis, K., Rodriguiz, R. M., Huang, X.-P., Norval, S., Sassano, M. F., Shin, A. I., Webster, L. A., et al. (2012) · Nature · doi:10.1038/nature11691 · Cited by 832
DeWire, S. M., Yamashita, D. S., Rominger, D. H., Liu, G., Cowan, C. L., Graczyk, T. M., Chen, X.-T., Pitis, P. M., Gotchev, D., Yuan, C., et al. (2013) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.201616 · Cited by 647
Cited by
Averting opioid-induced respiratory depression without affecting analgesia
Dahan, A., van der Schrier, R., Smith, T., Aarts, L., van Velzen, M., & Niesters, M. (2018) · Anesthesiology · doi:10.1097/aln.0000000000002184 · Cited by 115
Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists
Stahl, E. L., & Bohn, L. M. (2022) · Biochemistry · doi:10.1021/acs.biochem.1c00466 · Cited by 55
Metadata
- Authors
- Váradi, A., Marrone, G. F., Palmer, T. C., Narayan, A., Szabó, M. R., Le Rouzic, V., Grinnell, S. G., Subrath, J. J., Warner, E., Kalra, S., Hunkele, A., Pagirsky, J., Eans, S. O., Medina, J. M., Xu, J., Pan, Y.-X., Borics, A., Pasternak, G. W., McLaughlin, J. P., & Majumdar, S.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-09-02
- Volume
- 59
- Issue
- 18
- Pages
- 8381-8397
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2507665026
- Cited by
- 323
- References
- 3
- FWCI
- 28.51
- Type
- journal article
- Language
- en
- Open access
- green
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