U-47700

U-47700
Legal status
Legal status
Identifiers
CAS Number 82657-23-6
PubChem (CID) 13544016
ChemSpider 23113403 YesY
UNII 6IY4WX208T YesY
ChEMBL CHEMBL277572
Chemical and physical data
Formula C16H22Cl2N2O
Molar mass 329.27 g·mol−1
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

U-47700, street name pinky or pink, is an opioid analgesic drug developed by a team at Upjohn in the 1970s[1] that acts as a selective agonist of the µ-opioid receptor with a Kd value of 5.3 nM compared to 910 nM for the κ-opioid receptor[2][3] and has around 7.5 x the potency of morphine in animal models.[4][5][6]

U-47700 is a structural isomer of the earlier opioid AH-7921[7] and the result of a great deal of work elucidating the quantitative structure–activity relationship of the scaffold. Upjohn looked for the key moieties which gave the greatest activity[8] and posted over a dozen patents on related compounds, each optimizing one moiety[9][10][11][12][13][14][15][16] until they discovered that U-47700 was the most active.[17]

U-47700 became the lead compound of selective kappa-opioid receptor ligands such as U-50488, U-51754 (containing a single methylene spacer difference) and U-69,593, which share very similar structures.[18][2] Although not used medically, the selective kappa ligands are used in research.[19][20]

Side effects

U-47700 has never been studied on humans, but would be expected to produce effects similar to those of other potent opioid agonists, including strong analgesia, sedation, euphoria, constipation, itching and respiratory depression which could be harmful or fatal.[21][22][23][24][25][26][27] Tolerance and dependence would be expected to develop.[28]

Combined consumption of U-47700 and fentanyl caused one fatality in Belgium.[29][30] 17 opioid overdoses and several deaths in the USA had initially been associated with U-47700 in April 2016,[31] as of September 2016 at least 15 fatalities were confirmed.[32][33][34][35][36][37]

Legal status

Following its sale as a designer drug, U-47700 was made illegal in Sweden on 26 January 2016.[38]

U-47700 was emergency scheduled in Ohio on 3 May 2016 by executive order of Governor John Kasich.[39]

U-47700 was emergency scheduled in Florida on 27 September 2016 by an emergency rule of Florida Attorney General Pam Bondi.[40]

Responding to the imminent threat to public health and safety, the U.S. Drug Enforcement Administration has placed U-47700 into Schedule 1 of the Controlled Substances Act, effective November 14, 2016.[41]

See also

References

  1. ↑ Jacob Szmuszkovicz (4 July 1978). "Patent US4098904 - Analgesic N-(2-aminocycloaliphatic)benzamides".
  2. 1 2 Loew, G.; Lawson, J.; Toll, L.; Frenking, G.; Berzetei-Gurske, I.; Polgar, W. (1988). "Structure activity studies of two classes of β-amino-amides: the search for kappa-selective opioids" (PDF). NIDA Research Monograph. 90: 144–151. ISSN 1046-9516. PMID 2855852.
  3. ↑ Filizola, Marta; Villar, Hugo O.; Loew, Gilda H. (April 2001). "Differentiation of δ, μ, and κ opioid receptor agonists based on pharmacophore development and computed physicochemical properties". Journal of Computer-Aided Molecular Design. 15 (4): 297–307. doi:10.1023/A:1011187320095. ISSN 1573-4951. PMID 11349813.
  4. ↑ Cheney, B. Vernon; Szmuszkovicz, Jacob; Lahti, Robert A.; Zichi, Dominic A. (December 1985). "Factors affecting binding of trans-N-[2-(methylamino)cyclohexyl]benzamides at the primary morphine receptor". Journal of Medicinal Chemistry. 28 (12): 1853–1864. doi:10.1021/jm00150a017. PMID 2999404.
  5. ↑ Harper, N. J.; Veitch, G. B. A.; Wibberley, D. G. (November 1974). "1-(3,4-Dichlorobenzamidomethyl)cyclohexyldimethylamine and related compounds as potential analgesics". Journal of Medicinal Chemistry. 17 (11): 1188–1193. doi:10.1021/jm00257a012. PMID 4416926.
  6. ↑ Szmuszkovicz, Jacob; Von Voigtlander, Philip F. (October 1982). "Benzeneacetamide Amines: Structurally Novel Non-mµ Opioids". Journal of Medicinal Chemistry. 25 (10): 1125–1126. doi:10.1021/jm00352a005. ISSN 0022-2623. PMID 6128415.
  7. ↑ Brittain, R. T.; Kellett, D. N.; Neat, M. L.; Stables, R. (September 1973). "Proceedings: Anti-nociceptive effects in N-substituted cyclohexylmethylbenzamides.". British Journal of Pharmacology. 49 (1): 158P–159P. doi:10.1111/j.1476-5381.1973.tb08279.x. ISSN 0007-1188. PMC 1776456Freely accessible. PMID 4207044.
  8. ↑ Michalson, Erik T.; Szmuszkovicz, Jacob (1989). Medicinal agents incorporating the 1,2-diamine functionality. Progress in Drug Research. Progress in Drug Research. Birkhäuser Basel. pp. 135–149. doi:10.1007/978-3-0348-9146-2_6. ISBN 9783034891462. PMID 2687936.
  9. ↑ Darrell D. Mullins (28 June 1966). "Patent US US3258489 - N-(1-aminocyclohexylmethyl)anilines and N-(1-nitrocyclohexylmethyl)anilines".
  10. ↑ Norman James Harper; George Bryan Austin Veitch (17 August 1976). "Patent US3975443 - 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine".
  11. ↑ Jacob Szmuszkovicz Kalamazoo (3 March 1970). "Patent US3499033 - Ethers of α-phenyl-2-aminocycloalkanemethanols".
  12. ↑ Jacob Szmuszkovicz (5 May 1970). "Patent US3510492 - 2-anilino and 2-anilinomethyl cycloalkylamines".
  13. ↑ Ronald H. Rynbrandt; Louis L. Skaletzky (7 March 1972). "Patent US3647804 - Cycloalkanecarboxamides".
  14. ↑ W. Roll (23 July 1974). "Patent US3825595 - N-cyclopentyl-N-2-hydroxyalkyl-ring-substituted benzamides".
  15. ↑ Norman James Harper; George Bryan Austin Veitch (20 September 1977). "Patent US4049663 - Ethylene diamine derivatives".
  16. ↑ Robert J. Collins; Lester J. Kaplan; James H. Ludens; Philip F. Von Voigtlander (9 April 1982). "Patent US4463013 - Oxygen substituted amino-cyclohexyl-benzeneacetamides and -benzamides as water diuretic drugs".
  17. ↑ Casy, Alan F.; Parfitt, Robert T. (1986). Miscellaneous Groups of Analgesics. Opioid Analgesics. Springer US. pp. 385–403. doi:10.1007/978-1-4899-0585-7_11. ISBN 9781489905857.
  18. ↑ Szmuszkovicz, Jacob; Zhao, Shikai; Totleben, Michael J.; Mizsak, Stephen A.; Freeman, Jeremiah P. "Phenanthridone Analogs of the Opiate Agonist U-47,700 in the trans-1,2-Diaminocyclohexane Benzamide Series". Heterocycles. 52 (1): 325–332. doi:10.3987/com-99-s27.
  19. ↑ Szmuszkovicz, Jacob (1999). U-50,488 and the к receptor: A personalized account covering the period 1973 to 1990. Progress in Drug Research. Progress in Drug Research. Birkhäuser Basel. pp. 167–195. doi:10.1007/978-3-0348-8730-4_4. ISBN 9783034887304.
  20. ↑ Tsibulnikov, S. Yu; Maslov, L. N.; Mukhomedzyanov, A. V.; Krylatov, A. V.; Tsibulnikova, M. R.; Lishmanov, Yu B. (October 2015). "Prospects of Using of κ-Opioid Receptor Agonists U-50,488 and ICI 199,441 for Improving Heart Resistance to Ischemia/Reperfusion". Bulletin of Experimental Biology and Medicine. 159 (6): 718–721. doi:10.1007/s10517-015-3057-8. ISSN 1573-8221. PMID 26519268.
  21. ↑ Todd L. Davis (9 March 2016). "New Synthetic Opioid Surfaces in North Texas". NBCDFW.
  22. ↑ Jones, Matthew J.; Hernandez, Bradley S.; Janis, Gregory C.; Stellpflug, Samuel J. (2016). "A case of U-47700 overdose with laboratory confirmation and metabolite identification". Clinical Toxicology. doi:10.1080/15563650.2016.1209767. ISSN 1556-3650. PMID 27549165.
  23. ↑ Domanski, K.; Kleinschmidt, K. C.; Schulte, J. M.; Fleming, S.; Frazee, C.; Menendez, A.; Tavakoli, K. (2016). "Two cases of intoxication with new synthetic opioid, U-47700". Clinical Toxicology. doi:10.1080/15563650.2016.1209763. ISSN 1556-3650. PMID 27432224.
  24. ↑ Ruan, Xiulu; Chiravuri, Srinivas; Kaye, AlanD. (September 2016). "Comparing fatal cases involving U-47700". Forensic Science, Medicine, and Pathology. 12 (3): 369–371. doi:10.1007/s12024-016-9795-8. ISSN 1547-769X. PMID 27421264.
  25. ↑ Elliott, Simon P.; Brandt, Simon D.; Smith, Christopher (August 2016). "The first reported fatality associated with the synthetic opioid 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and implications for forensic analysis". Drug Testing and Analysis. 8 (8): 875–879. doi:10.1002/dta.1984. ISSN 1942-7611. PMID 27232154.
  26. ↑ Armenian, Patil; Olson, Alexander; Anaya, Andres; Kurtz, Alicia; Ruegner, Rawnica; Gerona, Roy R. "Fentanyl and a Novel Synthetic Opioid U-47700 Masquerading as Street "Norco" in Central California: A Case Report". Annals of Emergency Medicine. doi:10.1016/j.annemergmed.2016.06.014. PMID 27473610.
  27. ↑ Helander, Anders; Bäckberg, Matilda (2016). "New Psychoactive Substances (NPS) – the Hydra monster of recreational drugs". Clinical Toxicology. doi:10.1080/15563650.2016.1217003. ISSN 1556-3650. PMID 27549399.
  28. ↑ Kimergård, Andreas; Breindahl, Torben; Hindersson, Peter; Deluca, Paolo (October 2016). "Tampering of opioid analgesics: a serious challenge for public health?". Addiction. 111 (10): 1701–1702. doi:10.1111/add.13436. ISSN 1360-0443. PMID 27273814.
  29. ↑ Coopman, Vera; Blanckaert, Peter; Van Parys, Geert; Van Calenbergh, Serge; Cordonnier, Jan (September 2016). "A case of acute intoxication due to combined use of fentanyl and 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700)". Forensic Science International. 266: 68–72. doi:10.1016/j.forsciint.2016.05.001. PMID 27235591.
  30. ↑ "Twee doden in België door overdosis met fentanylpleisters" (in Dutch). Deredactie. 29 January 2016.
  31. ↑ Zalkind, Susan (11 April 2016). "Synthetic opiate makers stay step ahead of US drug laws as overdose cases rise". The Guardian. ISSN 0261-3077.
  32. ↑ Bill Draper (6 June 2016). "New synthetic drug U-47700 has states rushing to stop spread". Associated Press.
  33. ↑ Schneir, Aaron; Metushi, Imir G.; Sloane, Christian; Benaron, David J.; Fitzgerald, Robert L. (2016). "Near death from a novel synthetic opioid labeled U-47700: emergence of a new opioid class". Clinical Toxicology. doi:10.1080/15563650.2016.1209764. ISSN 1556-3650. PMID 27448790.
  34. ↑ Mohr, Amanda L. A.; Friscia, Melissa; Papsun, Donna; Kacinko, Sherri L.; Buzby, David; Logan, Barry K. (2016). "Analysis of Novel Synthetic Opioids U-47700, U-50488 and Furanyl Fentanyl by LC–MS/MS in Postmortem Casework". Journal of Analytical Toxicology. doi:10.1093/jat/bkw086. ISSN 1945-2403. PMID 27590036.
  35. ↑ "19 Recent Deaths Associated With Synthetic Opioids; State Officials Urge Awareness". NC Department of Health and Human Services. 24 March 2016.
  36. ↑ Drug Enforcement Administration (DEA) (7 September 2016). "Proposed Rule: Schedules of Controlled Substances: Temporary Placement of U-47700 Into Schedule I". Federal Register.
  37. ↑ "NMS Labs Announces Toxicological Confirmation of Hundreds of Deaths Involving Novel Designer Opioids in the United States". Business Wire. 14 September 2016.
  38. ↑ "31 nya ämnen kan klassas som narkotika eller hälsofarlig vara" (in Swedish). Folkhälsomyndigheten. November 2015.
  39. ↑ John R. Kasich (3 May 2016). "Executive Order 2016-01K" (PDF). Governor of Ohio.
  40. ↑ "News Release - Attorney General Bondi Outlaws Deadly Synthetic Drug". www.myfloridalegal.com. Retrieved 2016-11-02.
  41. ↑ DEA Public Affairs (November 11, 2016). "46 confirmed deaths linked to dangerous opioid in '15 and '16 spark emergency action". DEA.
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