Chemistry:Metkefamide

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Short description: Chemical compound
Metkefamide
Metkefamide.svg
Clinical data
ATC code
  • None
Pharmacokinetic data
Bioavailability30-35%[1]
Protein binding44-49%[2]
MetabolismHepatic[1]
Elimination half-life~60 minutes[3]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC29H40N6O6S
Molar mass600.74 g·mol−1
3D model (JSmol)

Metkefamide (INN; LY-127,623), or metkephamid acetate (USAN), but most frequently referred to simply as metkephamid, is a synthetic opioid pentapeptide and derivative of [Met]enkephalin with the amino acid sequence Tyr-D-Ala-Gly-Phe-(N-Me)-Met-NH2.[4] It behaves as a potent agonist of the δ- and μ-opioid receptors with roughly equipotent affinity,[5][6] and also has similarly high affinity as well as subtype-selectivity for the κ3-opioid receptor.[7][8]

Despite its peptidic nature, upon systemic administration, metkefamide rapidly penetrates the blood-brain-barrier and disperses into the central nervous system where it produces potent, centrally-mediated analgesic effects,[9] of which have been shown to be dependent on activity at both the μ- and δ-opioid receptors.[6][10] In addition, on account of modifications to the N- and C-terminals, metkefamide is highly stable against proteolytic degradation relative to many other opioid peptides.[3][11] As an example, while its parent peptide, [Met]enkephalin, has an in vivo half-life of merely seconds, metkefamide has a half-life of nearly 60 minutes, and upon intramuscular administration, has been shown to provide pain relief that lasts for hours.[3]

Likely on account of its δ-opioid activity, clinical trials have found metkefamide to possess less of a tendency for producing many of the undesirable side effects usually associated with conventional opioids such as respiratory depression, tolerance, and physical dependence.[6][12] However, it has been shown to cause some additional side effects that are considered unusual for standard opioid analgesics like sensations of heaviness in the extremities and nasal congestion—though these were not considered to be particularly distressing[9]—and it has also been shown to raise the seizure threshold in animals.[13] In any case, clinical development was not further pursued after phase I clinical studies and metkefamide never reached the pharmaceutical market.[14][15][16]

See also

References

  1. ↑ 1.0 1.1 "Protein-Protein Interaction Inhibitors". Amino Acids, Peptides and Proteins. Royal Society of Chemistry. 8 November 2000. p. 258. ISBN 978-0-85404-227-2. https://books.google.com/books?id=0m0hTecnchcC&pg=PA258. Retrieved 27 April 2012. 
  2. ↑ "Pharmacokinetics and Pharmacodynamics of Therapeutic Peptides and Proteins". Pharmaceutical Biotechnology: Drug Discovery and Clinical Applications. John Wiley & Sons. 13 June 2012. p. 346. ISBN 978-3-527-32994-6. https://books.google.com/books?id=A_VWwihjS1AC&pg=PA346. Retrieved 27 April 2012. 
  3. ↑ 3.0 3.1 3.2 "Synthesis of Peptides and Proteins by Chemical and Biotechnological Means". Peptide and Protein Drug Delivery. CRC Press. 1991. p. 90. ISBN 978-0-8247-7896-5. https://books.google.com/books?id=XM2_SX953W0C&pg=PA90. Retrieved 27 April 2012. 
  4. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer. 1999. p. 180. ISBN 978-0-7514-0499-9. https://books.google.com/books?id=mqaOMOtk61IC&pg=PA180. Retrieved 27 April 2012. 
  5. ↑ "Metkephamid (Tyr-D-ala-Gly-Phe-N(Me)Met-NH2), a potent opioid peptide: receptor binding and analgesic properties". Peptides 3 (5): 869–871. 1982. doi:10.1016/0196-9781(82)90029-8. PMID 6294639. 
  6. ↑ 6.0 6.1 6.2 "Metkephamid, a systemically active analog of methionine enkephalin with potent opioid alpha-receptor activity". Science 211 (4482): 603–605. February 1981. doi:10.1126/science.6256856. PMID 6256856. 
  7. ↑ "Opioids and the Control of Pain". Neurotherapeutics: Emerging Strategies. Contemporary Neuroscience. Humana Press. 1996. p. 172. doi:10.1007/978-1-59259-466-5_5. ISBN 978-0-89603-306-1. https://books.google.com/books?id=4dwchq3oHFQC&pg=PA172. Retrieved 27 April 2012. 
  8. ↑ "Kappa opiate receptor multiplicity: evidence for two U50,488-sensitive kappa 1 subtypes and a novel kappa 3 subtype". The Journal of Pharmacology and Experimental Therapeutics 251 (2): 461–468. November 1989. PMID 2553920. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2553920. 
  9. ↑ 9.0 9.1 "Analgesic efficacy of parenteral metkephamid acetate in treatment of postoperative pain". Lancet 1 (8286): 1374–1375. June 1982. doi:10.1016/s0140-6736(82)92497-7. PMID 6123675. 
  10. ↑ "Cross-tolerance studies distinguish morphine- and metkephamid-induced analgesia". Life Sciences 31 (12–13): 1201–1204. 1982. doi:10.1016/0024-3205(82)90342-3. PMID 6292609. 
  11. ↑ "Multifunctional Polymers for Peroral Delivery". Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and Development. CRC Press. 13 July 1999. p. 323. ISBN 978-0-8247-1995-1. https://books.google.com/books?id=d8-Eo7iGOTkC&pg=PA323. Retrieved 27 April 2012. 
  12. ↑ "Protein Structure". Fundamentals of Protein Biotechnology. CRC Press. 31 August 1990. p. 17. ISBN 978-0-8247-8346-4. https://books.google.com/books?id=a-er5mhepr8C&pg=PA17. Retrieved 27 April 2012. 
  13. ↑ "A selective role for delta-receptors in the regulation of opioid-induced changes in seizure threshold". Life Sciences 33 (Suppl 1): 603–606. 1983. doi:10.1016/0024-3205(83)90575-1. PMID 6319916. 
  14. ↑ "Neuropeptides and Their Processing: Targets for Drug Design". Annual Reports in Medicinal Chemistry. 22. Academic Press. 1 August 1987. p. 58. doi:10.1016/S0065-7743(08)61154-9. ISBN 978-0-12-040522-0. https://books.google.com/books?id=oJeTSJveeuAC&pg=PA58. Retrieved 27 April 2012. 
  15. ↑ "Treament Research". Drug Abuse and Drug Abuse Research (1991): The Third Triennial Report to Congress from the Secretary, Department of Health and Human Services. DIANE Publishing. 1 August 1999. p. 51. ISBN 978-0-7881-8196-2. https://books.google.com/books?id=-dmoEAVRCqAC&pg=PA51. Retrieved 27 April 2012. 
  16. ↑ Dictionary of Pharmacological Agents Volume 2. CRC Press. 1996-11-21. p. 1343. ISBN 978-0-412-46630-4. https://books.google.com/books?id=A0THacd46ZsC&pg=PA1023. Retrieved 26 April 2012. 



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