en BU72

BU72
Identifiers
	IUPAC name (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	173265-76-4 ;
PubChem CID	137348291;
IUPHAR/BPS	9363;
ChemSpider	9662011;
UNII	KVN8RP2FQX;
ChEMBL	ChEMBL4649916;
PDB ligand	VF1 (PDBe, RCSB PDB);
Chemical and physical data
Formula	C28H32N2O2
Molar mass	428.576 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES 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=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.

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, with a slow onset and long duration of action.^[3]^[4]

Chemistry

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] The stereochemistry has recently been revised, with the phenyl group in the (R) configuration.^[8]^[9] In the crystal structure, BU72 appears to bond to the receptor covalently,^[10]^[11] but this seems not to occur in vivo, since the compound binds reversibly, and preventing bond formation has no effect on affinity.^[1]

Synthesis:^[12]

References

^ ^a ^b ^c 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ Munro TA (April 2020). "Revised (β-phenyl) stereochemistry of ultrapotent μ opioid BU72". bioRxiv. doi:10.1101/2020.04.01.020883. S2CID 215551137.
^ 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.
^ 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.
^ 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.
^ 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.

[Huang_2015-1] 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] Munro TA (April 2020). "Revised (β-phenyl) stereochemistry of ultrapotent μ opioid BU72". bioRxiv. doi:10.1101/2020.04.01.020883. S2CID 215551137.

[9] 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.

[10] 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.

[11] 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.

[12] 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.

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BU72

Pharmacology

Chemistry

See also

References

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