Improved bioavailability to the brain of glycosylated Met-enkephalin analogs
The blood–brain barrier prevents the entry of many potentially therapeutic peptide drugs to the brain. Glycosylation has shown potential as a methodology for improving delivery to the CNS. Previous studies have shown improved bioavailability and improved centrally mediated analgesia of glycosylated...
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| Veröffentlicht in: | Brain research 2000-10, Vol.881 (1), p.37-46 |
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| creator | Egleton, Richard D Mitchell, Scott A Huber, Jason D Janders, Jaqueline Stropova, Dagmar Polt, Robin Yamamura, Henry I Hruby, Victor J Davis, Thomas P |
| description | The blood–brain barrier prevents the entry of many potentially therapeutic peptide drugs to the brain. Glycosylation has shown potential as a methodology for improving delivery to the CNS. Previous studies have shown improved bioavailability and improved centrally mediated analgesia of glycosylated opioids. In this study we investigate the effect of glycosylation on the cyclic opioid peptide [
d-Cys
2,5,Ser
6,Gly
7] enkephalin. The peptide was glycosylated on the Ser
6 via an O-linkage with various sugar moieties and alignments. The peptides were then investigated for receptor binding, physiochemical attributes, in situ brain uptake in female Sprague–Dawley rats and antinociception in male ICR mice. Glycosylation resulted in a slight decrease in affinity to the δ-opioid receptor, and mixed effect on binding to the μ-opioid receptor. There was a significant decrease in lipophilicity resulting from glycosylation and a slight reduction in binding to bovine serum albumin. In situ perfusion showed that brain uptake was improved by up to 98% for several of the glycosylated peptides, and the nociceptive profiles of the peptides, in general, followed the rank order of peptide entry to the brain with up to a 39-fold increase in A.U.C. |
| doi_str_mv | 10.1016/S0006-8993(00)02794-3 |
| format | Article |
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d-Cys
2,5,Ser
6,Gly
7] enkephalin. The peptide was glycosylated on the Ser
6 via an O-linkage with various sugar moieties and alignments. The peptides were then investigated for receptor binding, physiochemical attributes, in situ brain uptake in female Sprague–Dawley rats and antinociception in male ICR mice. Glycosylation resulted in a slight decrease in affinity to the δ-opioid receptor, and mixed effect on binding to the μ-opioid receptor. There was a significant decrease in lipophilicity resulting from glycosylation and a slight reduction in binding to bovine serum albumin. In situ perfusion showed that brain uptake was improved by up to 98% for several of the glycosylated peptides, and the nociceptive profiles of the peptides, in general, followed the rank order of peptide entry to the brain with up to a 39-fold increase in A.U.C.</description><identifier>ISSN: 0006-8993</identifier><identifier>EISSN: 1872-6240</identifier><identifier>DOI: 10.1016/S0006-8993(00)02794-3</identifier><identifier>PMID: 11033091</identifier><identifier>CODEN: BRREAP</identifier><language>eng</language><publisher>London: Elsevier B.V</publisher><subject>Animals ; Antinociception ; Bioavailability ; Biological and medical sciences ; Biological Availability ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - physiology ; Brain - metabolism ; Cattle ; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges ; Enkephalin, Methionine - analogs & derivatives ; Enkephalin, Methionine - pharmacokinetics ; Female ; Fundamental and applied biological sciences. Psychology ; Glycosylation ; Male ; Mice ; Pain Measurement - drug effects ; Peptide ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, delta - metabolism ; Structure activity ; Vertebrates: nervous system and sense organs</subject><ispartof>Brain research, 2000-10, Vol.881 (1), p.37-46</ispartof><rights>2000 Elsevier Science B.V.</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c420t-d19df39ec8b8c38d18f4210ba6ed248b59c20c762ba933c71f83e9900a6214ba3</citedby><cites>FETCH-LOGICAL-c420t-d19df39ec8b8c38d18f4210ba6ed248b59c20c762ba933c71f83e9900a6214ba3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0006-8993(00)02794-3$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=797547$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11033091$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Egleton, Richard D</creatorcontrib><creatorcontrib>Mitchell, Scott A</creatorcontrib><creatorcontrib>Huber, Jason D</creatorcontrib><creatorcontrib>Janders, Jaqueline</creatorcontrib><creatorcontrib>Stropova, Dagmar</creatorcontrib><creatorcontrib>Polt, Robin</creatorcontrib><creatorcontrib>Yamamura, Henry I</creatorcontrib><creatorcontrib>Hruby, Victor J</creatorcontrib><creatorcontrib>Davis, Thomas P</creatorcontrib><title>Improved bioavailability to the brain of glycosylated Met-enkephalin analogs</title><title>Brain research</title><addtitle>Brain Res</addtitle><description>The blood–brain barrier prevents the entry of many potentially therapeutic peptide drugs to the brain. Glycosylation has shown potential as a methodology for improving delivery to the CNS. Previous studies have shown improved bioavailability and improved centrally mediated analgesia of glycosylated opioids. In this study we investigate the effect of glycosylation on the cyclic opioid peptide [
d-Cys
2,5,Ser
6,Gly
7] enkephalin. The peptide was glycosylated on the Ser
6 via an O-linkage with various sugar moieties and alignments. The peptides were then investigated for receptor binding, physiochemical attributes, in situ brain uptake in female Sprague–Dawley rats and antinociception in male ICR mice. Glycosylation resulted in a slight decrease in affinity to the δ-opioid receptor, and mixed effect on binding to the μ-opioid receptor. There was a significant decrease in lipophilicity resulting from glycosylation and a slight reduction in binding to bovine serum albumin. In situ perfusion showed that brain uptake was improved by up to 98% for several of the glycosylated peptides, and the nociceptive profiles of the peptides, in general, followed the rank order of peptide entry to the brain with up to a 39-fold increase in A.U.C.</description><subject>Animals</subject><subject>Antinociception</subject><subject>Bioavailability</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Blood-Brain Barrier - physiology</subject><subject>Brain - metabolism</subject><subject>Cattle</subject><subject>Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges</subject><subject>Enkephalin, Methionine - analogs & derivatives</subject><subject>Enkephalin, Methionine - pharmacokinetics</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glycosylation</subject><subject>Male</subject><subject>Mice</subject><subject>Pain Measurement - drug effects</subject><subject>Peptide</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Opioid, delta - metabolism</subject><subject>Structure activity</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0006-8993</issn><issn>1872-6240</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1vEzEQQC0EoqHwE0ArISE4bBnbm7V9qlAFtFIQB-Bsjb2zrcFZB3sTKf--bhO1x55mRvPmQ4-xtxzOOPD-8y8A6FttjPwI8AmEMl0rn7EF10q0vejgOVs8ICfsVSl_aymlgZfshPOageELtrpab3La0dC4kHCHIaILMcz7Zk7NfEONyximJo3Nddz7VPYR5wr_oLml6R9tbjDWNk4Y03V5zV6MGAu9OcZT9ufb198Xl-3q5_eriy-r1ncC5nbgZhilIa-d9lIPXI-d4OCwp0F02i2NF-BVLxwaKb3io5ZkDAD2gncO5Sn7cNhbX_-_pTLbdSieYsSJ0rZYJaTUUpgnQa6UEFLrCi4PoM-plEyj3eSwxry3HOydb3vv297JtAD23reVde7d8cDWrWl4nDoKrsD7I4DFYxwzTj6UB04ZtexUpc4PFFVru0DZFh9o8jSETH62QwpPPHILsLab3Q</recordid><startdate>20001020</startdate><enddate>20001020</enddate><creator>Egleton, Richard D</creator><creator>Mitchell, Scott A</creator><creator>Huber, Jason D</creator><creator>Janders, Jaqueline</creator><creator>Stropova, Dagmar</creator><creator>Polt, Robin</creator><creator>Yamamura, Henry I</creator><creator>Hruby, Victor J</creator><creator>Davis, Thomas P</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><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>7TK</scope><scope>7X8</scope></search><sort><creationdate>20001020</creationdate><title>Improved bioavailability to the brain of glycosylated Met-enkephalin analogs</title><author>Egleton, Richard D ; Mitchell, Scott A ; Huber, Jason D ; Janders, Jaqueline ; Stropova, Dagmar ; Polt, Robin ; Yamamura, Henry I ; Hruby, Victor J ; Davis, Thomas P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c420t-d19df39ec8b8c38d18f4210ba6ed248b59c20c762ba933c71f83e9900a6214ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Animals</topic><topic>Antinociception</topic><topic>Bioavailability</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Blood-Brain Barrier - drug effects</topic><topic>Blood-Brain Barrier - physiology</topic><topic>Brain - metabolism</topic><topic>Cattle</topic><topic>Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges</topic><topic>Enkephalin, Methionine - analogs & derivatives</topic><topic>Enkephalin, Methionine - pharmacokinetics</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Glycosylation</topic><topic>Male</topic><topic>Mice</topic><topic>Pain Measurement - drug effects</topic><topic>Peptide</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Opioid, delta - metabolism</topic><topic>Structure activity</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Egleton, Richard D</creatorcontrib><creatorcontrib>Mitchell, Scott A</creatorcontrib><creatorcontrib>Huber, Jason D</creatorcontrib><creatorcontrib>Janders, Jaqueline</creatorcontrib><creatorcontrib>Stropova, Dagmar</creatorcontrib><creatorcontrib>Polt, Robin</creatorcontrib><creatorcontrib>Yamamura, Henry I</creatorcontrib><creatorcontrib>Hruby, Victor J</creatorcontrib><creatorcontrib>Davis, Thomas P</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Brain research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Egleton, Richard D</au><au>Mitchell, Scott A</au><au>Huber, Jason D</au><au>Janders, Jaqueline</au><au>Stropova, Dagmar</au><au>Polt, Robin</au><au>Yamamura, Henry I</au><au>Hruby, Victor J</au><au>Davis, Thomas P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Improved bioavailability to the brain of glycosylated Met-enkephalin analogs</atitle><jtitle>Brain research</jtitle><addtitle>Brain Res</addtitle><date>2000-10-20</date><risdate>2000</risdate><volume>881</volume><issue>1</issue><spage>37</spage><epage>46</epage><pages>37-46</pages><issn>0006-8993</issn><eissn>1872-6240</eissn><coden>BRREAP</coden><abstract>The blood–brain barrier prevents the entry of many potentially therapeutic peptide drugs to the brain. Glycosylation has shown potential as a methodology for improving delivery to the CNS. Previous studies have shown improved bioavailability and improved centrally mediated analgesia of glycosylated opioids. In this study we investigate the effect of glycosylation on the cyclic opioid peptide [
d-Cys
2,5,Ser
6,Gly
7] enkephalin. The peptide was glycosylated on the Ser
6 via an O-linkage with various sugar moieties and alignments. The peptides were then investigated for receptor binding, physiochemical attributes, in situ brain uptake in female Sprague–Dawley rats and antinociception in male ICR mice. Glycosylation resulted in a slight decrease in affinity to the δ-opioid receptor, and mixed effect on binding to the μ-opioid receptor. There was a significant decrease in lipophilicity resulting from glycosylation and a slight reduction in binding to bovine serum albumin. In situ perfusion showed that brain uptake was improved by up to 98% for several of the glycosylated peptides, and the nociceptive profiles of the peptides, in general, followed the rank order of peptide entry to the brain with up to a 39-fold increase in A.U.C.</abstract><cop>London</cop><cop>Amsterdam</cop><cop>New York, NY</cop><pub>Elsevier B.V</pub><pmid>11033091</pmid><doi>10.1016/S0006-8993(00)02794-3</doi><tpages>10</tpages></addata></record> |
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| subjects | Animals Antinociception Bioavailability Biological and medical sciences Biological Availability Blood-Brain Barrier - drug effects Blood-Brain Barrier - physiology Brain - metabolism Cattle Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges Enkephalin, Methionine - analogs & derivatives Enkephalin, Methionine - pharmacokinetics Female Fundamental and applied biological sciences. Psychology Glycosylation Male Mice Pain Measurement - drug effects Peptide Rats Rats, Sprague-Dawley Receptors, Opioid, delta - metabolism Structure activity Vertebrates: nervous system and sense organs |
| title | Improved bioavailability to the brain of glycosylated Met-enkephalin analogs |
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