Metkefamide Explained

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.^[1] It behaves as a potent agonist of the δ- and μ-opioid receptors with roughly equipotent affinity,^{[2] [3]} and also has similarly high affinity as well as subtype-selectivity for the κ₃-opioid receptor.^{[4] [5]}

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,^[6] of which have been shown to be dependent on activity at both the μ- and δ-opioid receptors.^[7] 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.^[8] 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.

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.^[9] 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—and it has also been shown to raise the seizure threshold in animals.^[10] In any case, clinical development was not further pursued after phase I clinical studies and metkefamide never reached the pharmaceutical market.^{[11] [12] [13]}

See also

• [Met]Enkephalin
• Frakefamide

Notes and References

1. Book: Morton I, Hall JM . Concise Dictionary of Pharmacological Agents: Properties and Synonyms . 27 April 2012 . 1999 . Springer . 978-0-7514-0499-9 . 180.
2. Burkhardt C, Frederickson RC, Pasternak GW . 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 . 6294639 . 10.1016/0196-9781(82)90029-8 . 3872497 .
3. Frederickson RC, Smithwick EL, Shuman R, Bemis KG . Metkephamid, a systemically active analog of methionine enkephalin with potent opioid alpha-receptor activity . Science . 211 . 4482 . 603–605 . February 1981 . 6256856 . 10.1126/science.6256856 .
4. Book: Paul D, Pasternak GW . Opioids and the Control of Pain . Pullan LM, Patel J . Neurotherapeutics: Emerging Strategies . Contemporary Neuroscience . https://books.google.com/books?id=4dwchq3oHFQC&pg=PA172 . 27 April 2012 . 1996 . Humana Press . 978-0-89603-306-1 . 10.1007/978-1-59259-466-5_5 . 172.
5. Clark JA, Liu L, Price M, Hersh B, Edelson M, Pasternak GW . 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 . 2553920 .
6. Calimlim JF, Wardell WM, Sriwatanakul K, Lasagna L, Cox C . Analgesic efficacy of parenteral metkephamid acetate in treatment of postoperative pain . Lancet . 1 . 8286 . 1374–1375 . June 1982 . 6123675 . 10.1016/s0140-6736(82)92497-7 . 9618418 .
7. Hynes MD, Frederickson RC . Cross-tolerance studies distinguish morphine- and metkephamid-induced analgesia . Life Sciences . 31 . 12–13 . 1201–1204 . 1982 . 6292609 . 10.1016/0024-3205(82)90342-3 .
8. Book: Luessen HL, Verhoef JC, deBoer HE, etal . Multifunctional Polymers for Peroral Delivery. Mathiowitz E, Chickering DE, Lehr CM . Claus-Michael Lehr . Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and Development . https://books.google.com/books?id=d8-Eo7iGOTkC&pg=PA323 . 27 April 2012 . 13 July 1999 . CRC Press . 978-0-8247-1995-1 . 323.
9. Book: Lehrman SR . Protein Structure . Stein S . Fundamentals of Protein Biotechnology . https://books.google.com/books?id=a-er5mhepr8C&pg=PA17 . 27 April 2012 . 31 August 1990 . CRC Press . 978-0-8247-8346-4 . 17.
10. Tortella FC, Robles LE, Holaday JW, Cowan A . A selective role for delta-receptors in the regulation of opioid-induced changes in seizure threshold . Life Sciences . 33 . Suppl 1 . 603–606 . 1983 . 6319916 . 10.1016/0024-3205(83)90575-1 .
11. Book: van Nispen JW, Pinder RM . Neuropeptides and Their Processing: Targets for Drug Design. Bailey DM . Annual Reports in Medicinal Chemistry . https://books.google.com/books?id=oJeTSJveeuAC&pg=PA58 . 27 April 2012 . 1 August 1987 . 22. Academic Press . 978-0-12-040522-0 . 10.1016/S0065-7743(08)61154-9 . 58.
12. Book: Embrey ML, Hartel CR . Treament Research . Drug Abuse and Drug Abuse Research (1991): The Third Triennial Report to Congress from the Secretary, Department of Health and Human Services . https://books.google.com/books?id=-dmoEAVRCqAC&pg=PA51 . 27 April 2012 . 1 August 1999 . DIANE Publishing . 978-0-7881-8196-2 . 51.
13. Book: Dictionary of Pharmacological Agents Volume 2 . 26 April 2012 . CRC Press . 978-0-412-46630-4 . 1343. 1996-11-21.