BU72
{{Short description|Opioid analgesic drug}}
{{Technical|date=March 2021}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| drug_name =
| type =
| 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
| image = BU72beta structure.png
| image_class = skin-invert-image
| alt =
| caption =
| tradename =
| MedlinePlus =
| licence_EU =
| licence_US =
| pregnancy_AU =
| pregnancy_category =
| legal_US =
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| bioavailability =
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| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 173265-76-4
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = KVN8RP2FQX
| PubChem = 137348291
| IUPHAR_ligand = 9363
| DrugBank =
| ChemSpiderID = 9662011
| ChEMBL = 4649916
| PDB_ligand = VF1
| C = 28
| H = 32
| N = 2
| O = 2
| 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
| StdInChI = 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
| StdInChIKey = 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. It also has extremely high efficacy, giving a stronger maximal effect than the standard full agonist DAMGO.{{cite journal | vauthors = Zhao J, Elgeti M, O'Brien ES, Sár CP, Ei Daibani A, Heng J, Sun X, White E, Che T, Hubbell WL, Kobilka BK, Chen C | title = Ligand efficacy modulates conformational dynamics of the µ-opioid receptor | journal = Nature | date = April 2024 | pmid = 38600384 | doi = 10.1038/s41586-024-07295-2 | doi-access = free | pmc = 11078757 }} 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.{{cite journal | vauthors = Neilan CL, Husbands SM, Breeden S, Ko MC, Aceto MD, Lewis JW, Woods JH, Traynor JR | title = Characterization of the complex morphinan derivative BU72 as a high efficacy, long-lasting mu-opioid receptor agonist | journal = European Journal of Pharmacology | volume = 499 | issue = 1–2 | pages = 107–116 | date = September 2004 | pmid = 15363957 | doi = 10.1016/j.ejphar.2004.07.097 }}{{cite journal | vauthors = Disney A, Olson KM, Shafer AM, Moore SC, Anand JP, Traynor JR, Husbands SM | title = Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose | journal = ACS Chemical Neuroscience | volume = 13 | issue = 21 | pages = 3108–3117 | date = November 2022 | pmid = 36223082 | pmc = 9634796 | doi = 10.1021/acschemneuro.2c00464 }}
Chemistry
BU72 was used to produce the first crystal structure of the active μ-opioid receptor,{{cite journal | vauthors = Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, Kato HE, Livingston KE, Thorsen TS, Kling RC, Granier S, Gmeiner P, Husbands SM, Traynor JR, Weis WI, Steyaert J, Dror RO, Kobilka BK | title = Structural insights into µ-opioid receptor activation | journal = Nature | volume = 524 | issue = 7565 | pages = 315–321 | date = August 2015 | pmid = 26245379 | pmc = 4639397 | doi = 10.1038/nature14886 | bibcode = 2015Natur.524..315H }} and is now widely used to model the activation process.{{cite journal | vauthors = Sounier R, Mas C, Steyaert J, Laeremans T, Manglik A, Huang W, Kobilka BK, Déméné H, Granier S | title = Propagation of conformational changes during μ-opioid receptor activation | journal = Nature | volume = 524 | issue = 7565 | pages = 375–378 | date = August 2015 | pmid = 26245377 | pmc = 4820006 | doi = 10.1038/nature14680 | bibcode = 2015Natur.524..375S }}{{cite journal | vauthors = Cheng JX, Cheng T, Li WH, Liu GX, Zhu WL, Tang Y | title = Computational insights into the G-protein-biased activation and inactivation mechanisms of the μ opioid receptor | journal = Acta Pharmacologica Sinica | volume = 39 | issue = 1 | pages = 154–164 | date = January 2018 | pmid = 29188799 | pmc = 5758664 | doi = 10.1038/aps.2017.158 | doi-access = free }}{{cite journal | vauthors = Sena DM, Cong X, Giorgetti A | title = Ligand based conformational space studies of the μ-opioid receptor | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1865 | issue = 3 | pages = 129838 | date = March 2021 | pmid = 33373630 | doi = 10.1016/j.bbagen.2020.129838 | s2cid = 229721515 }} The stereochemistry has recently been revised, with the phenyl group in the (R) configuration.{{cite journal | vauthors = Munro TA | title = Revised (β-phenyl) stereochemistry of ultrapotent μ opioid BU72. | journal = bioRxiv | date = April 2020 | doi = 10.1101/2020.04.01.020883 | s2cid = 215551137 }}{{cite journal | vauthors = Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, Kato HE, Livingston KE, Thorsen TS, Kling RC, Granier S, Gmeiner P, Husbands SM, Traynor JR, Weis WI, Steyaert J, Dror RO, Kobilka BK | title = Author Correction: Structural insights into μ-opioid receptor activation | journal = Nature | volume = 584 | issue = 7820 | pages = E16 | date = August 2020 | pmid = 32724208 | doi = 10.1038/s41586-020-2542-z | doi-access = free }} In the crystal structure, BU72 appears to bond to the receptor covalently,{{Cite journal | vauthors = Zou R, Wang X, Li S, Chan HS, Vogel H, Yuan S |date=2022 |title=The role of metal ions in G protein-coupled receptor signalling and drug discovery |journal=WIREs Computational Molecular Science |language=en |volume=12 |issue=2 |doi=10.1002/wcms.1565 |issn=1759-0876}}{{cite journal | vauthors = Munro TA | title = Reanalysis of a μ opioid receptor crystal structure reveals a covalent adduct with BU72 | journal = BMC Biology | volume = 21 | issue = 1 | pages = 213 | date = October 2023 | pmid = 37817141 | pmc = 10566028 | doi = 10.1186/s12915-023-01689-w | doi-access = free }} but this seems not to occur {{em|in vivo}}, since the compound binds reversibly, and preventing bond formation has no effect on affinity.
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