Dezocine

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Dezocine
Dezocine structure.svg
Systematic (IUPAC) name
(5R,11S,13R)-13-Amino-5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzo[10]annulen-3-ol
Clinical data
Trade names Dalgan
AHFS/Drugs.com Micromedex Detailed Consumer Information
Routes of
administration
Intravenous
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Metabolism Hepatic
Biological half-life 2.2 hours
Identifiers
CAS Number 53648-55-8 YesY
ATC code N02AX03 (WHO)
PubChem CID 3033053
DrugBank DB01209 N
ChemSpider 2297867 YesY
UNII VHX8K5SV4X YesY
KEGG D00838 YesY
ChEBI CHEBI:4474 YesY
ChEMBL CHEMBL1685 YesY
Synonyms WY-16225
Chemical data
Formula C16H23NO
Molar mass 245.36 g/mol
 NYesY (what is this?)  (verify)

Dezocine (INN, USAN) (brand name Dalgan) is a marketed opioid analgesic of the benzomorphan group.[1] First synthesized in 1970,[2] it acts at mu-, delta-, and kappa-opioid receptors. Dezocine is a mixed agonist/antagonist of opioid receptors. It is related to other benzomorphans such as pentazocine, with a similar profile of effects that include analgesia and euphoria.[3] Unlike many other benzomorphans however, it is a silent antagonist of the κ-opioid receptor, and in accordance, does not produce side effects such as dysphoria or hallucinations at any dose.[4]

History[edit]

Dezocine was patented by American Home Products Corp. in 1978. Clinical trials ran from 1979-1985, before its approval by the U.S. Food and Drug Administration (FDA) in 1986. As of 2011,[5] dezocine's usage is discontinued in the United States.

Synthesis[edit]

Dezocine [(−)-13β-amino-5,6,7,8,9,10,11,12-octahydro-5α-methyl-5,11-methanobenxocyclodecen-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.[6]

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 tertbutylate.[7] 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.

Legal status in United States[edit]

As of 2011, dezocine is not used in the United States or Canada. It is not commercially available in either of these countries,[8] nor is it offered as a prescribed analgesic for postoperative care. In China however, it is commonly used after surgery.[9]

Pharmacology[edit]

Target action[edit]

Dezocine has an intramuscular bioavailability of 97%.[10] It has a mean t1/2 α of fewer than two minutes, and its half-life is 2.2 hours. Its binding affinity varies with regards to the receptor type, as it acts as a partial agonist primarily on mu-opioid receptors. At kappa-opioid receptors, it acts as an antagonist.[11] Overall, it has a high efficacy as an analgesic.

With regards to its potency, it has a Bmax of 3326 fmol/mg of protein in HEK cells.[9] Dezocine is five times as potent as pethidine and one-fifth as potent as butorphanol.[12]

Mechanism of action at the mu opioid receptor

Dezocine is unusual among opiates as it is one of the only primary amines known to be an active opioid (along with bisnortilidine, an active metabolite of tilidine). It is a mixed agonist–antagonist as with other drugs in this class,[13] and 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.[14]

Dezocine possesses affinities (Ki) of 3.7 nM, 31.9 nM, and 527 nM for the μ-, κ-, and δ-opioid receptors (MOR, KOR, and DOR), respectively.[15] It is a partial agonist of the MOR and a silent antagonist of the KOR.[15] In addition to its opioid actions, 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]

Due to its partial agonist nature at the MOR, dezocine has significantly reduced side effects relative to opioid analgesics acting as full agonists of the MOR 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 MOR agonists (including weak partial agonists like buprenorphine) and for reasons that are not fully clear, it is apparently non-addictive.[15]

Administration[edit]

Dezocine is generally administered intravenously. It can also be administered in intramuscular doses, and is given singularly rather than continuously. Dezocine has been found to be an effective painkiller comparable to meperidine (pethidine),[16] and so is a more effective analgesic than pentazocine, but causes relatively more respiratory depression than pentazocine.[17] It is a useful drug for the treatment of pain,[18] but side effects such as dizziness limit its clinical application,[19] and it can produce opioid withdrawal syndrome in patients already dependent on other opioids.[20]

Uses[edit]

Prescription[edit]

Dezocine is generally administered intravenously (as Dalgan) to relieve post-operative pain in patients. Because of its high efficacy, it is often administered at a base dose of 0.1 mg/kg. Respiratory depression, a side-effect of dezocine, reaches a ceiling at 0.3-0.4 mg/kg. It has potent analgesic results, and greater pain-relieving ability than morphine, codeine, and pethidine.[9]

Side effects[edit]

Because decozine has mixed agonist/antagonist effects on mu-, delta-, and kappa-opioid receptors, it has a lowered dependence potential than purely agonistic opiates. 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 0.3-0.4 mg/kg.

Side effects at lower doses include mild gastrointestinal discomfort and dizziness. It is often administered in post-operative laproscopy patients as an alternative to fentanyl.

See also[edit]

References[edit]

  1. ^ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 368–. ISBN 978-1-4757-2085-3. 
  2. ^ "Espacenet". Espacenet Patent Search. 
  3. ^ Zacny, J. P.; Lichtor, J. L.; de Wit, H. (1992). "Subjective, Behavioral, and Physiologic Responses to Intravenous Dezocine in Healthy Volunteers". Anesthesia and Analgesia. 74 (4): 523–530. doi:10.1213/00000539-199204000-00010. PMID 1348168. 
  4. ^ Westmoreland, Cheryl (August 1991). "Opioid agonist-antagonists". Current Opinion in Anesthesiology. 4 (4). 
  5. ^ "FDA Drugs". 
  6. ^ Malis, JL; Rosenthale, ME; Gluckman, MI (September 1975). "Animal pharmacology of Wy-16,225, a new analgesic agent.". The Journal of Pharmacology and Experimental Therapeutics. 194 (3): 488–98. PMID 808600. 
  7. ^ Freed, ME; Potoski, JR; Freed, EH; Conklin, GL; Malis, JL (June 1973). "Bridged aminotetralins as novel potent analgesic sunstances.". Journal of Medicinal Chemistry. 16 (6): 595–9. doi:10.1021/jm00264a003. PMID 4714986. 
  8. ^ "=FDA Drugs". 
  9. ^ a b c Gharagozlou, P; Demirci, H; David Clark, J; Lameh, J (Jan 4, 2003). "Activity of opioid ligands in cells expressing cloned mu opioid receptors.". BMC pharmacology. 3: 1. PMC 140036free to read. PMID 12513698. 
  10. ^ Locniskar, A; Greenblatt, DJ; Zinny, MA (1986). "Pharmacokinetics of dezocine, a new analgesic: effect of dose and route of administration.". European journal of clinical pharmacology. 30 (1): 121–3. doi:10.1007/bf00614208. PMID 3709625. 
  11. ^ Gharagozlou, P; Hashemi, E; DeLorey, TM; Clark, JD; Lameh, J (Jan 25, 2006). "Pharmacological profiles of opioid ligands at kappa opioid receptors.". BMC pharmacology. 6: 3. doi:10.1186/1471-2210-6-3. PMC 1403760free to read. PMID 16433932. 
  12. ^ O'Brien, JJ; Benfield, P (August 1989). "Dezocine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.". Drugs. 38 (2): 226–48. doi:10.2165/00003495-198938020-00005. PMID 2670517. 
  13. ^ Young, A. M.; Stephens, K. R.; Hein, D. W.; Woods, J. H. (1984). "Reinforcing and Discriminative Stimulus Properties of Mixed Agonist-Antagonist Opioids". Journal of Pharmacology and Experimental Therapeutics. 229 (1): 118–126. PMID 6142942. 
  14. ^ Romagnoli, A.; Keats, A. S. (1984). "Ceiling Respiratory Depression by Dezocine". Clinical Pharmacology and Therapeutics. 35 (3): 367–373. doi:10.1038/clpt.1984.45. PMID 6421529. 
  15. ^ a b c d e Liu, Renyu; Huang, Xi-Ping; Yeliseev, Alexei; Xi, Jin; Roth, Bryan L. (2014). "Novel Molecular Targets of Dezocine and Their Clinical Implications". Anesthesiology. 120 (3): 714–723. doi:10.1097/ALN.0000000000000076. ISSN 0003-3022. 
  16. ^ Camu, F.; Gepts, E. (1979). "Analgesic Properties of Dezocine for Relief of Postoperative Pain". Acta Anaesthesiologica Belgica. 30 (Suppl): 183–191. PMID 398127. 
  17. ^ Wuest, H. P.; Bellville, J. W. (1979). "The Respiratory Effects of Dezocine and Pentazocine in Man". Journal of Clinical Pharmacology. 19 (4): 205–210. doi:10.1002/j.1552-4604.1979.tb01653.x. PMID 438355. 
  18. ^ O'Brien, J. J.; Benfield, P. (1989). "Dezocine. A Preliminary Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy". Drugs. 38 (2): 226–248. doi:10.2165/00003495-198938020-00005. PMID 2670517. 
  19. ^ Oosterlinck, W.; Verbaeys, A. (1980). "Preliminary Clinical Experience with Dezocine, a New Potent Analgesic". Current Medical Research and Opinion. 6 (7): 472–474. doi:10.1185/03007998009109470. PMID 7363647. 
  20. ^ Strain, E. C.; Preston, K. L.; Liebson, I. A.; Bigelow, G. E. (1996). "Opioid Antagonist Effects of Dezocine in Opioid-Dependent Humans". Clinical Pharmacology and Therapeutics. 60 (2): 206–217. doi:10.1016/S0009-9236(96)90137-X. PMID 8823239.