Chemistry:BU72

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BU72 is an extremely potent opioid used in pharmacological research.

Pharmacology

BU72 is an agonist for the μ-opioid receptor with exceptionally high binding affinity and potency, comparable to carfentanil.[1] It also has extremely high efficacy, giving a stronger maximal effect than the standard full agonist DAMGO.[2] In animal studies, it was found to be a potent analgesic (giving pain relief at very low doses), with a slow onset and long duration of action.[3][4]

BU72 was used to produce the first crystal structure of the active μ-opioid receptor,[1] and is now widely used to model the activation process.[5][6][7] In the crystal structure, BU72 appears to bond to the receptor covalently,[8][9] but this seems to be an experimental artifact, since the compound binds reversibly, and preventing bond formation has no effect on affinity.[1]

Chemistry

BU72 original proposed structure ((S)-phenyl epimer)

BU72 is synthesized in several steps from thebaine.[10] Its stereochemistry has recently been revised, with the phenyl group in the (R) configuration.[11][12]

See also

References

  1. ↑ 1.0 1.1 1.2 "Structural insights into µ-opioid receptor activation". Nature 524 (7565): 315–321. August 2015. doi:10.1038/nature14886. PMID 26245379. Bibcode: 2015Natur.524..315H. 
  2. ↑ "Ligand efficacy modulates conformational dynamics of the µ-opioid receptor". Nature 629 (8011): 474–480. April 2024. doi:10.1038/s41586-024-07295-2. PMID 38600384. Bibcode: 2024Natur.629..474Z. 
  3. ↑ "Characterization of the complex morphinan derivative BU72 as a high efficacy, long-lasting mu-opioid receptor agonist". European Journal of Pharmacology 499 (1–2): 107–116. September 2004. doi:10.1016/j.ejphar.2004.07.097. PMID 15363957. 
  4. ↑ "Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose". ACS Chemical Neuroscience 13 (21): 3108–3117. November 2022. doi:10.1021/acschemneuro.2c00464. PMID 36223082. 
  5. ↑ "Propagation of conformational changes during μ-opioid receptor activation". Nature 524 (7565): 375–378. August 2015. doi:10.1038/nature14680. PMID 26245377. Bibcode: 2015Natur.524..375S. 
  6. ↑ "Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor". Acta Pharmacologica Sinica 39 (1): 154–164. January 2018. doi:10.1038/aps.2017.158. PMID 29188799. 
  7. ↑ "Ligand based conformational space studies of the μ-opioid receptor". Biochimica et Biophysica Acta (BBA) - General Subjects 1865 (3). March 2021. doi:10.1016/j.bbagen.2020.129838. PMID 33373630. 
  8. ↑ "The role of metal ions in G protein-coupled receptor signalling and drug discovery" (in en). WIREs Computational Molecular Science 12 (2). 2022. doi:10.1002/wcms.1565. ISSN 1759-0876. http://infoscience.epfl.ch/record/287849. 
  9. ↑ "Reanalysis of a μ opioid receptor crystal structure reveals a covalent adduct with BU72". BMC Biology 21 (1). October 2023. doi:10.1186/s12915-023-01689-w. PMID 37817141. 
  10. ↑ "Morphinan cyclic imines and pyrrolidines containing a constrained phenyl group: High affinity opioid agonists". Bioorganic & Medicinal Chemistry Letters 5 (24): 2969–2974. December 1995. doi:10.1016/0960-894X(95)00522-1. 
  11. ↑ Munro TA (April 2020). "Revised (β-phenyl) stereochemistry of ultrapotent μ opioid BU72". bioRxiv 10.1101/2020.04.01.020883.
  12. ↑ "Author Correction: Structural insights into μ-opioid receptor activation". Nature 584 (7820): E16. August 2020. doi:10.1038/s41586-020-2542-z. PMID 32724208. 



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