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
AHFS/Drugs.com Micromedex Detailed Consumer Information
Legal status Discontinued[1]
Routes Intravenous
Pharmacokinetic data
Metabolism Hepatic
Half-life 2.2 hours
Identifiers
CAS number 53648-55-8 YesY
ATC code N02AX03
PubChem CID 3033053
DrugBank DB01209
ChemSpider 2297867 YesY
UNII VHX8K5SV4X YesY
KEGG D00838 YesY
ChEBI CHEBI:4474 YesY
ChEMBL CHEMBL1685 YesY
Synonyms WY-16,225
Chemical data
Formula C16H23NO 
Mol. mass 245.36 g/mol
 N (what is this?)  (verify)

Dezocine (DalganTM WY16225)is an opiate analgesic. First synthesized in 1970,[2] it acts at mu-, delta-, and kappa-opioid receptors. Dezocine acts as a mixed agonist/antagonist of opioid receptors. It is related to pentazocine, with a similar profile of effects that include analgesic action and euphoria at low doses,[3] but produces dysphoria and hallucinations at high doses, most likely due to action at κ-opioid receptors.[4][5]

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,[6] 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.[7]

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.[8] 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 hydroxylamide hydrochloride, to yield an oxime. A reduction reaction in hydrogen gas produces an isomeric mixture, from which the final product (XII) 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,[9] nor is it offered as a prescribed analgesic for postoperative care. In China, it is commonly used after surgery.[10]

Chemistry[edit]

Target action[edit]

Dezocine has a bioavailability of 97%.[11] 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.[12] 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.[10] Dezocine is five times as potent as pethidine and one-fifth as potent as butorphanol.[13]

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,[14] 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.[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.[10] However, naltrexone is a more potent analgesic than dezocine, and may be prescribed in its place.

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. At relatively high doses, it has been found to produce hallucinations. It is often administered in post-operative laproscopy patients as an alternative to fentanyl.

See also[edit]

References[edit]

  1. ^ "Dezocine". Drugs@FDA. 
  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. ^ Jacobs, A. M.; Youngblood, F. (1992). "Opioid Receptor Affinity for Agonist-Antagonist Analgesics". Journal of the American Podiatric Medical Association 82 (10): 520–524. doi:10.7547/87507315-82-10-520. PMID 1361946. 
  5. ^ Gharagozlou, P.; Hashemi, E.; DeLorey, T. M.; Clark, J. D.; Lameh, J. (2006). "Pharmacological Profiles of Opioid Ligands at Kappa Opioid Receptors" (pdf). BMC Pharmacology 6: 3. doi:10.1186/1471-2210-6-3. PMC 1403760. PMID 16433932. 
  6. ^ "FDA Drugs". 
  7. ^ 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. 
  8. ^ Freed, ME; Potoski, JR; Freed, EH; Conklin, GL; Malis, JL (June 1973). "Bridged aminotetralins as novel potent analgesic sunstances.". Journal of Medical Chemistry 16 (6): 595–9. doi:10.1021/jm00264a003. PMID 4714986. 
  9. ^ "=FDA Drugs". 
  10. ^ 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 140036. PMID 12513698. 
  11. ^ 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. 
  12. ^ 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 1403760. PMID 16433932. 
  13. ^ 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. PMID 2670517. 
  14. ^ 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. 
  15. ^ Romagnoli, A.; Keats, A. S. (1984). "Ceiling Respiratory Depression by Dezocine". Clinical Pharmacology and Therapeutics 35 (3): 367–373. PMID 6421529. 
  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. 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.