Chemistry:Dezocine

From HandWiki
Short description: Opioid analgesic
Dezocine
Dezocine structure.svg
Dezocine 3D BS.png
Clinical data
Trade namesDalgan
Other namesWY-16225
AHFS/Drugs.comMicromedex Detailed Consumer Information
Routes of
administration		Intravenous infusion, intramuscular injection[1]
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
MetabolismHepatic
Elimination half-life2.2 hours
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC16H23NO
Molar mass245.366 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Dezocine, sold under the brand name Dalgan, is an atypical opioid analgesic which is used in the treatment of pain.[1][2] It is used by intravenous infusion and intramuscular injection.[1][2]

Dezocine is an opioid receptor modulator, acting as a partial agonist of the μ- and κ-opioid receptors.[2] It has a similar profile of effects to related opioids acting at the μ-opioid receptor, including analgesia and euphoria.[2][3] Unlike other opioids acting at the κ-opioid receptor however, dezocine does not produce side effects such as dysphoria or hallucinations at any therapeutically used dose.[4]

Dezocine was first synthesized in 1970.[5] It was introduced for medical use in the United States in 1986 but was not marketed in other countries.[2][6] Dezocine was discontinued in the United States in 2011 with no official reason given.[2] However, it has become one of the most widely used analgesics in China .[2] In light of the opioid epidemic, dezocine has seen a resurgence in use and interest.[2]

Medical uses

Dezocine is generally administered intravenously (as Dalgan) to relieve post-operative pain in patients.[1] It can also be administered in intramuscular doses, and is given once rather than continuously. It is often administered in post-operative laparoscopy patients as an alternative to fentanyl. Dezocine has potent analgesic effects, and comparable or greater pain-relieving ability than morphine, codeine, and pethidine (meperidine).[7][8] It is a more effective analgesic than pentazocine, but causes relatively more respiratory depression than pentazocine.[9] Dezocine is a useful drug for the treatment of pain,[1] but side effects such as dizziness limit its clinical application,[10] and it can produce opioid withdrawal syndrome in patients already dependent on other opioids.[11] Because of its high efficacy, dezocine is often administered at a base dose of 0.1 mg/kg. Respiratory depression, a side effect of dezocine, reaches a ceiling at 0.3 to 0.4 mg/kg.

Side effects

Side effects at lower doses include mild gastrointestinal discomfort and dizziness. Because decozine has mixed agonist/antagonist effects at the opioid receptors, it has a lowered dependence potential than purely agonistic opioids. It can be prescribed, therefore, in small doses over an extended period of time without causing patients to develop and sustain an addiction. Its efficacy as an analgesic is dose-dependent; however, it displays a ceiling effect in induced respiratory depression at 0.3 to 0.4 mg/kg.

Pharmacology

Pharmacodynamics

Opioid Opioid receptor affinity (Ki, nM)
MOR KOR DOR
Dezocine 3.67 ± 0.7 31.9 ± 1.9 527 ± 70
Morphine 2.8 ± 0.2 55.96 ± 6.99 648.8 ± 59.7

Dezocine acts as an opioid receptor receptor modulator.[2] It is specifically a mixed agonist–antagonist or partial agonist of the μ- and κ-opioid receptors.[2][12][13][14] Dezocine could also act as a biased agonist of the μ-opioid receptor, although more research is needed to confirm this.[2] The binding affinity of dezocine varies depending on the opioid receptor, with it having the highest affinity for the μ-opioid receptor, intermediate affinity for the κ-opioid receptor, and the lowest affinity for the δ-opioid receptor.[2] In addition to its opioid activity, dezocine has been found to act as a serotonin–norepinephrine reuptake inhibitor (SNRI), with pIC50 values of 5.86 for the serotonin transporter (SERT) and 5.68 for the norepinephrine transporter (NET).[15][16] These actions theoretically might contribute to its analgesic efficacy.[2]

Dezocine is five times as potent as pethidine and one-fifth as potent as butorphanol as an analgesic.[1] Due to its partial agonist nature at the μ-opioid receptor, dezocine has significantly reduced side effects relative to opioid analgesics acting as full agonists of the receptor such as morphine.[15] Moreover, dezocine is not a controlled substance and there are no reports of addiction related to its use, indicating that, unlike virtually all other clinically employed μ-opioid receptor agonists (including weak partial agonists like buprenorphine), and for reasons that are not fully clear, it is apparently non-addictive.[15] This unique benefit makes long-term low-dose treatment of chronic pain and/or opioid dependence with dezocine more feasible than with most other opioids. Despite having a stronger respiratory depressant effect than morphine, dezocine shows a ceiling effect on its respiratory depressive action so above a certain dose this effect does not get any more severe.[17]

Pharmacokinetics

Dezocine has an bioavailability by intramuscular injection of 97%.[18] It has a mean t1/2α of fewer than two minutes, and its biological half-life is 2.2 hours.[citation needed]

Chemistry

Dezocine has a structure similar to the benzomorphan group of opioids. Dezocine is unusual among opioids as it is one of the only primary amines known to be active as an opioid (along with bisnortilidine, an active metabolite of tilidine).[2][additional citation(s) needed]

Synthesis

Dezocine [(−)-13β-amino-5,6,7,8,9,10,11,12-octahydro-5α-methyl-5,11-methanobenzocyclodecen-31-ol, hydrobromide] is a pale white crystal powder. It has no apparent odor. The salt is soluble at 20 mg/ml, and a 2% solution has a pH of 4.6.[19]

The synthesis of dezocine begins with the condensation of 1-methyl-7-methoxy-2-tetralone with 1,5-dibromopentane through use of NaH or potassium tert-butoxide.[20] This yields 1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone, which is then cyclized with NaH to produce 5-methyl-3-methoxy-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-13-one. The product is then treated with hydroxylamine hydrochloride, to yield an oxime. A reduction reaction in hydrogen gas produces an isomeric mixture, from which the final product is crystallized and cleaved with HBr.

History

Dezocine was patented by American Home Products Corp. in 1978. Clinical trials ran from 1979 to 1985, before its approval by the U.S. Food and Drug Administration (FDA) in 1986. As of 2011,[21] dezocine's usage is discontinued in the United States, but it is still widely used in some other countries such as China .[2][22]

Society and culture

Generic names

Dezocine is the generic name of the drug and its INN and USAN.[23][24][25][6]

Brand names

The major brand name of dezocine is Dalgan.[6]

Availability

In 2000, dezocine was listed as being marketed only in the United States .[6] It has since been marketed in China .[2] Dezocine was discontinued in the United States in 2011.[2]

Legal status

As of 2011, dezocine is not used in the United States or Canada. It is not commercially available in either of these countries,[21] nor is it offered as a prescribed analgesic for postoperative care. In China however, it is commonly used after surgery.[7]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Dezocine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy". Drugs 38 (2): 226–48. August 1989. doi:10.2165/00003495-198938020-00005. PMID 2670517. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 ""I'll Be Back": The Resurrection of Dezocine". ACS Med Chem Lett 12 (6): 961–968. June 2021. doi:10.1021/acsmedchemlett.1c00233. PMID 34141081. 
  3. ↑ "Subjective, behavioral, and physiologic responses to intravenous dezocine in healthy volunteers". Anesthesia and Analgesia 74 (4): 523–30. April 1992. doi:10.1213/00000539-199204000-00010. PMID 1348168. 
  4. ↑ "Opioid agonist-antagonists". Current Opinion in Anesthesiology 4 (4): 556–562. August 1991. doi:10.1097/00001503-199108000-00017. https://dx.doi.org/10.1097/00001503-199108000-00017. 
  5. ↑ "Espacenet". Espacenet Patent Search. http://worldwide.espacenet.com/publicationDetails/biblio?CC=DE&NR=2159324&KC=&FT=E&locale=en_EP. 
  6. ↑ 6.0 6.1 6.2 6.3 Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society. ed. Index Nominum 2000: International Drug Directory. Taylor & Francis. p. 320. ISBN 9783887630751. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA320. 
  7. ↑ 7.0 7.1 "Activity of opioid ligands in cells expressing cloned mu opioid receptors". BMC Pharmacology 3: 1. January 2003. doi:10.1186/1471-2210-3-1. PMID 12513698. 
  8. ↑ "Analgesic properties of dezocine for relief of postoperative pain". Acta Anaesthesiologica Belgica 30 (Suppl): 183–91. 1979. PMID 398127. 
  9. ↑ "The respiratory effects of dezocine and pentazocine in man". Journal of Clinical Pharmacology 19 (4): 205–10. April 1979. doi:10.1002/j.1552-4604.1979.tb01653.x. PMID 438355. 
  10. ↑ "Preliminary clinical experience with dezocine, a new potent analgesic". Current Medical Research and Opinion 6 (7): 472–4. 1980. doi:10.1185/03007998009109470. PMID 7363647. 
  11. ↑ "Opioid antagonist effects of dezocine in opioid-dependent humans". Clinical Pharmacology and Therapeutics 60 (2): 206–17. August 1996. doi:10.1016/S0009-9236(96)90137-X. PMID 8823239. 
  12. ↑ "Pharmacological Characterization of Dezocine, a Potent Analgesic Acting as a κ Partial Agonist and μ Partial Agonist". Sci Rep 8 (1): 14087. September 2018. doi:10.1038/s41598-018-32568-y. PMID 30237513. Bibcode: 2018NatSR...814087W. 
  13. ↑ "Pharmacological profiles of opioid ligands at kappa opioid receptors". BMC Pharmacology 6: 3. January 2006. doi:10.1186/1471-2210-6-3. PMID 16433932. 
  14. ↑ "Reinforcing and discriminative stimulus properties of mixed agonist-antagonist opioids". The Journal of Pharmacology and Experimental Therapeutics 229 (1): 118–26. April 1984. PMID 6142942. 
  15. ↑ 15.0 15.1 15.2 Cite error: Invalid <ref> tag; no text was provided for refs named LiuHuang2014
  16. ↑ "Dezocine exhibits antihypersensitivity activities in neuropathy through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition". Scientific Reports 7: 43137. February 2017. doi:10.1038/srep43137. PMID 28230181. Bibcode: 2017NatSR...743137W. 
  17. ↑ "Ceiling respiratory depression by dezocine". Clinical Pharmacology and Therapeutics 35 (3): 367–73. March 1984. doi:10.1038/clpt.1984.45. PMID 6421529. 
  18. ↑ "Pharmacokinetics of dezocine, a new analgesic: effect of dose and route of administration". European Journal of Clinical Pharmacology 30 (1): 121–3. 1986. doi:10.1007/bf00614208. PMID 3709625. 
  19. ↑ "Animal pharmacology of Wy-16,225, a new analgesic agent". The Journal of Pharmacology and Experimental Therapeutics 194 (3): 488–98. September 1975. PMID 808600. 
  20. ↑ "Bridged aminotetralins as novel potent analgesic sunstances". Journal of Medicinal Chemistry 16 (6): 595–9. June 1973. doi:10.1021/jm00264a003. PMID 4714986. 
  21. ↑ 21.0 21.1 "FDA Drugs". http://fdadrugs.legalview.com/legal-issue/dalgan. 
  22. ↑ "Comparison of the efficacy and safety between dezocine injection and morphine injection for persistence of pain in Chinese cancer patients: a meta-analysis". Bioscience Reports 37 (3). June 2017. doi:10.1042/BSR20170243. PMID 28533424. 
  23. ↑ The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 368–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA368. 
  24. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 2012. p. 96. ISBN 9789401144391. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA96. 
  25. ↑ Medicinal Chemistry. New Age International. 2005. p. 268. ISBN 9788122415650. https://books.google.com/books?id=07g30rxCA0EC&pg=PA268. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Dezocine&oldid=3333417"