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Metkefamide

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From Wikipedia, the free encyclopedia

Chemical compound

Pharmaceutical compound

Metkefamide
Clinical data

ATC code	None
Pharmacokinetic data
Bioavailability	30-35%^[1]
Protein binding	44-49%^[2]
Metabolism	Hepatic^[1]
Eliminationhalf-life	~60 minutes^[3]
Identifiers
IUPAC name L-tyrosyl-D-alanylglycyl-L-phenylalanyl-N²-methyl-L-methioninamide
CAS Number	66960-34-7 66960-35-8 (acetate)
PubChemCID	5464184
ChemSpider	4576570
UNII	MNL20FXH9Y
CompTox Dashboard(EPA)	DTXSID30985694
Chemical and physical data
Formula	C₂₉H₄₀N₆O₆S
Molar mass	600.74 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES O=C(N)[C@@H](N(C(=O)[C@@H](NC(=O)CNC(=O)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C)Cc2ccccc2)C)CCSC
InChI InChI=1S/C29H40N6O6S/c1-18(33-28(40)22(30)15-20-9-11-21(36)12-10-20)27(39)32-17-25(37)34-23(16-19-7-5-4-6-8-19)29(41)35(2)24(26(31)38)13-14-42-3/h4-12,18,22-24,36H,13-17,30H2,1-3H3,(H2,31,38)(H,32,39)(H,33,40)(H,34,37)/t18-,22+,23+,24+/m1/s1 Key:FWDIKROEWJOQIQ-JMBSJVKXSA-N

Metkefamide (INN;LY-127,623), ormetkephamid acetate (USAN), but most frequently referred to simply asmetkephamid, is asynthetic opioid pentapeptide and derivative of[Met]enkephalin with theamino acid sequence Tyr-D-Ala-Gly-Phe-(N-Me)-Met-NH₂.^[4] It behaves as apotent agonist of theδ- andμ-opioid receptors with roughly equipotentaffinity,^[5]^[6] and also has similarly high affinity as well as subtype-selectivity for theκ₃-opioid receptor.^[7]^[8]

Despite itspeptidic nature, uponsystemic administration, metkefamide rapidly penetrates theblood-brain-barrier and disperses into thecentral nervous system where it produces potent, centrally-mediatedanalgesic effects^[9] 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 theN- andC-terminals, metkefamide is highly stable againstproteolytic degradation relative to many other opioid peptides.^[3]^[11] As an example, while its parent peptide, [Met]enkephalin, has anin vivohalf-life of merely seconds, metkefamide has a half-life of nearly 60 minutes, and uponintramuscular administration, has been shown to providepain 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 undesirableside effects usually associated with conventional opioids such asrespiratory depression,tolerance, andphysical dependence.^[6]^[12] However, it has been shown to cause some additional side effects that are considered unusual for standard opioid analgesics, likesensations of heaviness in the extremities andnasal congestion—though these were not considered to be particularly distressing^[9]—and it has also been shown to raise theseizure threshold in animals.^[13] In any case, clinical development was not further pursued afterphase I clinical studies and metkefamide never reached the pharmaceutical market.^[14]^[15]^[16]

References

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^^a ^bDavies JS (8 November 2000)."Protein-Protein Interaction Inhibitors".Amino Acids, Peptides and Proteins. Royal Society of Chemistry. p. 258.ISBN 978-0-85404-227-2. Retrieved27 April 2012.
^Zheng Y, Meibohm B (13 June 2012)."Pharmacokinetics and Pharmacodynamics of Therapeutic Peptides and Proteins". In Kayser O, Warzecha H (eds.).Pharmaceutical Biotechnology: Drug Discovery and Clinical Applications. John Wiley & Sons. p. 346.ISBN 978-3-527-32994-6. Retrieved27 April 2012.
^^a ^b ^cGesellchen PD, Santerre RF (1991)."Synthesis of Peptides and Proteins by Chemical and Biotechnological Means". In Lee VH (ed.).Peptide and Protein Drug Delivery. CRC Press. p. 90.ISBN 978-0-8247-7896-5. Retrieved27 April 2012.
^Morton I, Hall JM (1999).Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer. p. 180.ISBN 978-0-7514-0499-9. Retrieved27 April 2012.
^Burkhardt C, Frederickson RC, Pasternak GW (1982). "Metkephamid (Tyr-D-ala-Gly-Phe-N(Me)Met-NH2), a potent opioid peptide: receptor binding and analgesic properties".Peptides.3 (5):869–871.doi:10.1016/0196-9781(82)90029-8.PMID 6294639.S2CID 3872497.
^^a ^b ^cFrederickson RC, Smithwick EL, Shuman R, Bemis KG (February 1981). "Metkephamid, a systemically active analog of methionine enkephalin with potent opioid alpha-receptor activity".Science.211 (4482):603–605.doi:10.1126/science.6256856.PMID 6256856.
^Paul D, Pasternak GW (1996)."Opioids and the Control of Pain". In Pullan LM, Patel J (eds.).Neurotherapeutics: Emerging Strategies. Contemporary Neuroscience. Humana Press. p. 172.doi:10.1007/978-1-59259-466-5_5.ISBN 978-0-89603-306-1. Retrieved27 April 2012.
^Clark JA, Liu L, Price M, Hersh B, Edelson M, Pasternak GW (November 1989)."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.PMID 2553920.
^^a ^bCalimlim JF, Wardell WM, Sriwatanakul K, Lasagna L, Cox C (June 1982). "Analgesic efficacy of parenteral metkephamid acetate in treatment of postoperative pain".Lancet.1 (8286):1374–1375.doi:10.1016/s0140-6736(82)92497-7.PMID 6123675.S2CID 9618418.
^Hynes MD, Frederickson RC (1982). "Cross-tolerance studies distinguish morphine- and metkephamid-induced analgesia".Life Sciences.31 (12–13):1201–1204.doi:10.1016/0024-3205(82)90342-3.PMID 6292609.
^Luessen HL, Verhoef JC,deBoer HE, et al. (13 July 1999)."Multifunctional Polymers for Peroral Delivery". In Mathiowitz E, Chickering DE, Lehr CM (eds.).Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and Development. CRC Press. p. 323.ISBN 978-0-8247-1995-1. Retrieved27 April 2012.
^Lehrman SR (31 August 1990)."Protein Structure". In Stein S (ed.).Fundamentals of Protein Biotechnology. CRC Press. p. 17.ISBN 978-0-8247-8346-4. Retrieved27 April 2012.
^Tortella FC, Robles LE, Holaday JW, Cowan A (1983). "A selective role for delta-receptors in the regulation of opioid-induced changes in seizure threshold".Life Sciences.33 (Suppl 1):603–606.doi:10.1016/0024-3205(83)90575-1.PMID 6319916.
^van Nispen JW, Pinder RM (1 August 1987)."Neuropeptides and Their Processing: Targets for Drug Design". In Bailey DM (ed.).Annual Reports in Medicinal Chemistry. Vol. 22. Academic Press. p. 58.doi:10.1016/S0065-7743(08)61154-9.ISBN 978-0-12-040522-0. Retrieved27 April 2012.
^Embrey ML, Hartel CR (1 August 1999)."Treatment 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. p. 51.ISBN 978-0-7881-8196-2. Retrieved27 April 2012.
^Dictionary of Pharmacological Agents Volume 2. CRC Press. 1996-11-21. p. 1343.ISBN 978-0-412-46630-4. Retrieved26 April 2012.