BU72

Last updated

BU72
BU72beta structure.png
Identifiers
  • (2R,3S,3aR,5aR,6R,11bR,11cS)-3a-methoxy-3,14-dimethyl-2-phenyl-2,3,3a,6,7,11c-hexahydro-1H-6,11b-(epiminoethano)-3,5a-methanonaphtho[2,1-g]indol-10-ol
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
PDB ligand
Chemical and physical data
Formula C28H32N2O2
Molar mass 428.576 g·mol−1
3D model (JSmol)
  • CO[C@]12C=C[C@]34C[C@@]1(C)[C@H](N[C@H]2[C@@]35CCN(C)[C@@H]4Cc6ccc(O)cc56)c7ccccc7
  • InChI=InChI=1S/C28H32N2O2/c1-25-17-26-11-12-28(25,32-3)24(29-23(25)18-7-5-4-6-8-18)27(26)13-14-30(2)22(26)15-19-9-10-20(31)16-21(19)27/h4-12,16,22-24,29,31H,13-15,17H2,1-3H3/t22-,23-,24+,25+,26-,27+,28+/m1/s1
  • Key:RGJHUVJQGAAZLK-GKTFKBBASA-N

BU72 is an extremely potent opioid used in pharmacological research.

Contents

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 structure.png
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 2 3 Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, et al. (August 2015). "Structural insights into µ-opioid receptor activation". Nature. 524 (7565): 315–321. Bibcode:2015Natur.524..315H. doi:10.1038/nature14886. PMC   4639397 . PMID   26245379.
  2. ↑ Zhao J, Elgeti M, O'Brien ES, Sár CP, Ei Daibani A, Heng J, et al. (April 2024). "Ligand efficacy modulates conformational dynamics of the µ-opioid receptor". Nature. doi: 10.1038/s41586-024-07295-2 . PMC   11078757 . PMID   38600384.
  3. ↑ Neilan CL, Husbands SM, Breeden S, Ko MC, Aceto MD, Lewis JW, et al. (September 2004). "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. doi:10.1016/j.ejphar.2004.07.097. PMID   15363957.
  4. ↑ Disney A, Olson KM, Shafer AM, Moore SC, Anand JP, Traynor JR, et al. (November 2022). "Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose". ACS Chemical Neuroscience. 13 (21): 3108–3117. doi:10.1021/acschemneuro.2c00464. PMC   9634796 . PMID   36223082.
  5. ↑ Sounier R, Mas C, Steyaert J, Laeremans T, Manglik A, Huang W, et al. (August 2015). "Propagation of conformational changes during μ-opioid receptor activation". Nature. 524 (7565): 375–378. Bibcode:2015Natur.524..375S. doi:10.1038/nature14680. PMC   4820006 . PMID   26245377.
  6. ↑ Cheng JX, Cheng T, Li WH, Liu GX, Zhu WL, Tang Y (January 2018). "Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor". Acta Pharmacologica Sinica. 39 (1): 154–164. doi: 10.1038/aps.2017.158 . PMC   5758664 . PMID   29188799.
  7. ↑ Sena DM, Cong X, Giorgetti A (March 2021). "Ligand based conformational space studies of the μ-opioid receptor". Biochimica et Biophysica Acta (BBA) - General Subjects. 1865 (3): 129838. doi:10.1016/j.bbagen.2020.129838. PMID   33373630. S2CID   229721515.
  8. ↑ Zou R, Wang X, Li S, Chan HS, Vogel H, Yuan S (2022). "The role of metal ions in G protein-coupled receptor signalling and drug discovery". WIREs Computational Molecular Science. 12 (2). doi:10.1002/wcms.1565. ISSN   1759-0876.
  9. ↑ Munro TA (October 2023). "Reanalysis of a μ opioid receptor crystal structure reveals a covalent adduct with BU72". BMC Biology. 21 (1): 213. doi: 10.1186/s12915-023-01689-w . PMC   10566028 . PMID   37817141.
  10. ↑ Husbands, S. M., Lewis, J. W. (December 1995). "Morphinan cyclic imines and pyrrolidines containing a constrained phenyl group: High affinity opioid agonists". Bioorganic & Medicinal Chemistry Letters. 5 (24): 2969–2974. doi:10.1016/0960-894X(95)00522-1.
  11. ↑ Munro TA (April 2020). "Revised (β-phenyl) stereochemistry of ultrapotent μ opioid BU72". bioRxiv. doi: 10.1101/2020.04.01.020883 . S2CID   215551137.
  12. ↑ Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, et al. (August 2020). "Author Correction: Structural insights into μ-opioid receptor activation". Nature. 584 (7820): E16. doi: 10.1038/s41586-020-2542-z . PMID   32724208.
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