Synthesis and Biological Evaluation of an Orally Active Glycosylated Endomorphin-1
The endogenous opioid peptide endomorphin-1 (1) was modified by attachment of lactose to the N-terminus via a succinamic acid spacer to produce compound 2. The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor bi...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-06, Vol.55 (12), p.5859-5867 |
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| container_issue | 12 |
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| container_title | Journal of medicinal chemistry |
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| creator | Varamini, Pegah Mansfeld, Friederike M Blanchfield, Joanne T Wyse, Bruce D Smith, Maree T Toth, Istvan |
| description | The endogenous opioid peptide endomorphin-1 (1) was modified by attachment of lactose to the N-terminus via a succinamic acid spacer to produce compound 2. The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor binding affinity and agonist activity. Analogue 2 produced dose-dependent antinociceptive activity following intravenous administration in a chronic constriction injury (CCI) rat model of neuropathic pain with an ED50 of 8.3 (±0.8) μmol/kg. The corresponding ED50 for morphine was 2.6 (±1.4) μmol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED50 = 19.6 (±1.2) μmol/kg), which was comparable with that of morphine (ED50 = 20.7 (±3.6) μmol/kg). Antineuropathic effects of analogue 2 were significantly attenuated by pretreatment of animals with the opioid antagonist naloxone, confirming opioid receptor-mediated analgesia. In contrast to morphine, no significant constipation was produced by compound 2 after oral administration. |
| doi_str_mv | 10.1021/jm300418d |
| format | Article |
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The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor binding affinity and agonist activity. Analogue 2 produced dose-dependent antinociceptive activity following intravenous administration in a chronic constriction injury (CCI) rat model of neuropathic pain with an ED50 of 8.3 (±0.8) μmol/kg. The corresponding ED50 for morphine was 2.6 (±1.4) μmol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED50 = 19.6 (±1.2) μmol/kg), which was comparable with that of morphine (ED50 = 20.7 (±3.6) μmol/kg). Antineuropathic effects of analogue 2 were significantly attenuated by pretreatment of animals with the opioid antagonist naloxone, confirming opioid receptor-mediated analgesia. In contrast to morphine, no significant constipation was produced by compound 2 after oral administration.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm300418d</identifier><identifier>PMID: 22680612</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Absorption ; Administration, Oral ; Analgesics, Opioid - adverse effects ; Analgesics, Opioid - chemical synthesis ; Analgesics, Opioid - metabolism ; Analgesics, Opioid - pharmacology ; Animals ; Chemistry Techniques, Synthetic ; CHO Cells ; Constipation - chemically induced ; Cricetinae ; Cricetulus ; Glycosylation ; Male ; Naloxone - pharmacology ; Narcotic Antagonists ; Neuralgia - drug therapy ; Oligopeptides - adverse effects ; Oligopeptides - chemical synthesis ; Oligopeptides - metabolism ; Oligopeptides - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid - metabolism</subject><ispartof>Journal of medicinal chemistry, 2012-06, Vol.55 (12), p.5859-5867</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-897c4735970f22e449ec900685cebd36cf8fd877530e493d7c58978f4213d4a73</citedby><cites>FETCH-LOGICAL-a315t-897c4735970f22e449ec900685cebd36cf8fd877530e493d7c58978f4213d4a73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm300418d$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm300418d$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27074,27922,27923,56736,56786</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22680612$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Varamini, Pegah</creatorcontrib><creatorcontrib>Mansfeld, Friederike M</creatorcontrib><creatorcontrib>Blanchfield, Joanne T</creatorcontrib><creatorcontrib>Wyse, Bruce D</creatorcontrib><creatorcontrib>Smith, Maree T</creatorcontrib><creatorcontrib>Toth, Istvan</creatorcontrib><title>Synthesis and Biological Evaluation of an Orally Active Glycosylated Endomorphin-1</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The endogenous opioid peptide endomorphin-1 (1) was modified by attachment of lactose to the N-terminus via a succinamic acid spacer to produce compound 2. The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor binding affinity and agonist activity. Analogue 2 produced dose-dependent antinociceptive activity following intravenous administration in a chronic constriction injury (CCI) rat model of neuropathic pain with an ED50 of 8.3 (±0.8) μmol/kg. The corresponding ED50 for morphine was 2.6 (±1.4) μmol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED50 = 19.6 (±1.2) μmol/kg), which was comparable with that of morphine (ED50 = 20.7 (±3.6) μmol/kg). Antineuropathic effects of analogue 2 were significantly attenuated by pretreatment of animals with the opioid antagonist naloxone, confirming opioid receptor-mediated analgesia. In contrast to morphine, no significant constipation was produced by compound 2 after oral administration.</description><subject>Absorption</subject><subject>Administration, Oral</subject><subject>Analgesics, Opioid - adverse effects</subject><subject>Analgesics, Opioid - chemical synthesis</subject><subject>Analgesics, Opioid - metabolism</subject><subject>Analgesics, Opioid - pharmacology</subject><subject>Animals</subject><subject>Chemistry Techniques, Synthetic</subject><subject>CHO Cells</subject><subject>Constipation - chemically induced</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Glycosylation</subject><subject>Male</subject><subject>Naloxone - pharmacology</subject><subject>Narcotic Antagonists</subject><subject>Neuralgia - drug therapy</subject><subject>Oligopeptides - adverse effects</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - metabolism</subject><subject>Oligopeptides - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Opioid - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0D1PwzAQBmALgaAUBv4A8oIEQ-D8kdgZS1UKUqVKfMyRazvgyolLnFTKvyeopRPTDffcK92L0BWBewKUPKwrBsCJNEdoRFIKCZfAj9EIgNKEZpSdofMY1wDACGWn6IzSTEJG6Ai9vvV1-2Wji1jVBj-64MOn08rj2Vb5TrUu1DiUwxIvG-V9jye6dVuL577XIfZetdbgWW1CFZrNl6sTcoFOSuWjvdzPMfp4mr1Pn5PFcv4ynSwSxUjaJjIXmguW5gJKSi3nudU5QCZTbVeGZbqUpZFCpAwsz5kROh1OZMkpYYYrwcbodpe7acJ3Z2NbVC5q672qbehiMVRDZQqpoAO921HdhBgbWxabxlWq6Qf060hxqHCw1_vYblVZc5B_nQ3gZgeUjsU6dE09fPlP0A-xFHZb</recordid><startdate>20120628</startdate><enddate>20120628</enddate><creator>Varamini, Pegah</creator><creator>Mansfeld, Friederike M</creator><creator>Blanchfield, Joanne T</creator><creator>Wyse, Bruce D</creator><creator>Smith, Maree T</creator><creator>Toth, Istvan</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20120628</creationdate><title>Synthesis and Biological Evaluation of an Orally Active Glycosylated Endomorphin-1</title><author>Varamini, Pegah ; Mansfeld, Friederike M ; Blanchfield, Joanne T ; Wyse, Bruce D ; Smith, Maree T ; Toth, Istvan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-897c4735970f22e449ec900685cebd36cf8fd877530e493d7c58978f4213d4a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Absorption</topic><topic>Administration, Oral</topic><topic>Analgesics, Opioid - adverse effects</topic><topic>Analgesics, Opioid - chemical synthesis</topic><topic>Analgesics, Opioid - metabolism</topic><topic>Analgesics, Opioid - pharmacology</topic><topic>Animals</topic><topic>Chemistry Techniques, Synthetic</topic><topic>CHO Cells</topic><topic>Constipation - chemically induced</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Glycosylation</topic><topic>Male</topic><topic>Naloxone - pharmacology</topic><topic>Narcotic Antagonists</topic><topic>Neuralgia - drug therapy</topic><topic>Oligopeptides - adverse effects</topic><topic>Oligopeptides - chemical synthesis</topic><topic>Oligopeptides - metabolism</topic><topic>Oligopeptides - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Opioid - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Varamini, Pegah</creatorcontrib><creatorcontrib>Mansfeld, Friederike M</creatorcontrib><creatorcontrib>Blanchfield, Joanne T</creatorcontrib><creatorcontrib>Wyse, Bruce D</creatorcontrib><creatorcontrib>Smith, Maree T</creatorcontrib><creatorcontrib>Toth, Istvan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Varamini, Pegah</au><au>Mansfeld, Friederike M</au><au>Blanchfield, Joanne T</au><au>Wyse, Bruce D</au><au>Smith, Maree T</au><au>Toth, Istvan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Biological Evaluation of an Orally Active Glycosylated Endomorphin-1</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-06-28</date><risdate>2012</risdate><volume>55</volume><issue>12</issue><spage>5859</spage><epage>5867</epage><pages>5859-5867</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The endogenous opioid peptide endomorphin-1 (1) was modified by attachment of lactose to the N-terminus via a succinamic acid spacer to produce compound 2. The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor binding affinity and agonist activity. Analogue 2 produced dose-dependent antinociceptive activity following intravenous administration in a chronic constriction injury (CCI) rat model of neuropathic pain with an ED50 of 8.3 (±0.8) μmol/kg. The corresponding ED50 for morphine was 2.6 (±1.4) μmol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED50 = 19.6 (±1.2) μmol/kg), which was comparable with that of morphine (ED50 = 20.7 (±3.6) μmol/kg). Antineuropathic effects of analogue 2 were significantly attenuated by pretreatment of animals with the opioid antagonist naloxone, confirming opioid receptor-mediated analgesia. In contrast to morphine, no significant constipation was produced by compound 2 after oral administration.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22680612</pmid><doi>10.1021/jm300418d</doi><tpages>9</tpages></addata></record> |
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| subjects | Absorption Administration, Oral Analgesics, Opioid - adverse effects Analgesics, Opioid - chemical synthesis Analgesics, Opioid - metabolism Analgesics, Opioid - pharmacology Animals Chemistry Techniques, Synthetic CHO Cells Constipation - chemically induced Cricetinae Cricetulus Glycosylation Male Naloxone - pharmacology Narcotic Antagonists Neuralgia - drug therapy Oligopeptides - adverse effects Oligopeptides - chemical synthesis Oligopeptides - metabolism Oligopeptides - pharmacology Rats Rats, Sprague-Dawley Receptors, Opioid - metabolism |
| title | Synthesis and Biological Evaluation of an Orally Active Glycosylated Endomorphin-1 |
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