Synthesis, biological activity and resistance to proteolytic digestion of new cyclic dermorphin/deltorphin analogues
A series of novel cyclic ureidopeptides, analogues of dermorphine/deltorphine tetrapeptide, were synthesized by solid phase peptide synthesis and/or in solution. The antinociceptive activity of N-substituted amides 1–10 was evaluated using hot-plate and tail-flick tests. Analogue 1 showed significan...
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| Veröffentlicht in: | European journal of medicinal chemistry 2013-05, Vol.63, p.457-467 |
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| creator | Bańkowski, Krzysztof Witkowska, Ewa Michalak, Olga M. Sidoryk, Katarzyna Szymanek, Ewa Antkowiak, Bożena Paluch, Małgorzata Filip, Katarzyna E. Cebrat, Marek Setner, Bartosz Szewczuk, Zbigniew Stefanowicz, Piotr Cmoch, Piotr Izdebski, Jan |
| description | A series of novel cyclic ureidopeptides, analogues of dermorphine/deltorphine tetrapeptide, were synthesized by solid phase peptide synthesis and/or in solution. The antinociceptive activity of N-substituted amides 1–10 was evaluated using hot-plate and tail-flick tests. Analogue 1 showed significant, stronger than morphine, antinociceptive effect after systemic applications. All analogues were also tested for their in vitro resistance to proteolysis by means of mass spectroscopy and it was found that all substituted amides 1–10 showed full stability during incubation with large excess of chymotrypsin and pepsin. Compound 1 is a lead molecule for further evaluation.
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► Novel cyclic ureidopeptides analogues of dermorphin/deltorphin were synthesized. ► Their in vivo antinociceptive activity and resistance to proteolysis were evaluated. ► N-substituted amides with D-amino acid showed extremely high proteolytic stability. ► Analogue 1 showed significant antinociceptive effect after systemic applications. |
| doi_str_mv | 10.1016/j.ejmech.2013.02.019 |
| format | Article |
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► Novel cyclic ureidopeptides analogues of dermorphin/deltorphin were synthesized. ► Their in vivo antinociceptive activity and resistance to proteolysis were evaluated. ► N-substituted amides with D-amino acid showed extremely high proteolytic stability. ► Analogue 1 showed significant antinociceptive effect after systemic applications.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2013.02.019</identifier><identifier>PMID: 23523659</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Analgesics, Opioid - chemical synthesis ; Analgesics, Opioid - chemistry ; Analgesics, Opioid - pharmacology ; Animals ; Antinociceptive effect ; Chymotrypsin - metabolism ; Cyclic opioid peptides ; Dermorphin/deltorphin analogues ; Hot Temperature - adverse effects ; Hydrolysis ; Hyperalgesia - etiology ; Hyperalgesia - physiopathology ; Hyperalgesia - prevention & control ; Indoles ; Male ; Mice ; Mice, Inbred BALB C ; Models, Chemical ; Molecular Structure ; Oligopeptides - chemical synthesis ; Oligopeptides - chemistry ; Oligopeptides - pharmacology ; Opioid Peptides - chemical synthesis ; Opioid Peptides - chemistry ; Opioid Peptides - pharmacology ; Pepsin A - metabolism ; Peptide synthesis ; Proteolysis ; Spectrometry, Mass, Electrospray Ionization ; Stability to proteolytic enzymes ; Styrenes</subject><ispartof>European journal of medicinal chemistry, 2013-05, Vol.63, p.457-467</ispartof><rights>2013 Elsevier Masson SAS</rights><rights>Copyright © 2013 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-a30cc29f3557fa58858fe2f36ae479bca4eacc3051c86f1368cdd84137c414743</citedby><cites>FETCH-LOGICAL-c362t-a30cc29f3557fa58858fe2f36ae479bca4eacc3051c86f1368cdd84137c414743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2013.02.019$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23523659$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bańkowski, Krzysztof</creatorcontrib><creatorcontrib>Witkowska, Ewa</creatorcontrib><creatorcontrib>Michalak, Olga M.</creatorcontrib><creatorcontrib>Sidoryk, Katarzyna</creatorcontrib><creatorcontrib>Szymanek, Ewa</creatorcontrib><creatorcontrib>Antkowiak, Bożena</creatorcontrib><creatorcontrib>Paluch, Małgorzata</creatorcontrib><creatorcontrib>Filip, Katarzyna E.</creatorcontrib><creatorcontrib>Cebrat, Marek</creatorcontrib><creatorcontrib>Setner, Bartosz</creatorcontrib><creatorcontrib>Szewczuk, Zbigniew</creatorcontrib><creatorcontrib>Stefanowicz, Piotr</creatorcontrib><creatorcontrib>Cmoch, Piotr</creatorcontrib><creatorcontrib>Izdebski, Jan</creatorcontrib><title>Synthesis, biological activity and resistance to proteolytic digestion of new cyclic dermorphin/deltorphin analogues</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>A series of novel cyclic ureidopeptides, analogues of dermorphine/deltorphine tetrapeptide, were synthesized by solid phase peptide synthesis and/or in solution. The antinociceptive activity of N-substituted amides 1–10 was evaluated using hot-plate and tail-flick tests. Analogue 1 showed significant, stronger than morphine, antinociceptive effect after systemic applications. All analogues were also tested for their in vitro resistance to proteolysis by means of mass spectroscopy and it was found that all substituted amides 1–10 showed full stability during incubation with large excess of chymotrypsin and pepsin. Compound 1 is a lead molecule for further evaluation.
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► Novel cyclic ureidopeptides analogues of dermorphin/deltorphin were synthesized. ► Their in vivo antinociceptive activity and resistance to proteolysis were evaluated. ► N-substituted amides with D-amino acid showed extremely high proteolytic stability. ► Analogue 1 showed significant antinociceptive effect after systemic applications.</description><subject>Analgesics, Opioid - chemical synthesis</subject><subject>Analgesics, Opioid - chemistry</subject><subject>Analgesics, Opioid - pharmacology</subject><subject>Animals</subject><subject>Antinociceptive effect</subject><subject>Chymotrypsin - metabolism</subject><subject>Cyclic opioid peptides</subject><subject>Dermorphin/deltorphin analogues</subject><subject>Hot Temperature - adverse effects</subject><subject>Hydrolysis</subject><subject>Hyperalgesia - etiology</subject><subject>Hyperalgesia - physiopathology</subject><subject>Hyperalgesia - prevention & control</subject><subject>Indoles</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Models, Chemical</subject><subject>Molecular Structure</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - pharmacology</subject><subject>Opioid Peptides - chemical synthesis</subject><subject>Opioid Peptides - chemistry</subject><subject>Opioid Peptides - pharmacology</subject><subject>Pepsin A - metabolism</subject><subject>Peptide synthesis</subject><subject>Proteolysis</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><subject>Stability to proteolytic enzymes</subject><subject>Styrenes</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1OHDEQhS2UCAaSG0SRl1nQjX_7Z4OEUCCRkFgE1panuprxqLs92B6ivg1nycniUUOWWbnkeq9e1UfIF85Kznh1sS1xOyJsSsG4LJkoGW-PyIrXVVNIodUHsmJCyEILqU7IaYxbxpiuGDsmJ0Lm30q3K7L_NU9pg9HFc7p2fvBPDuxALST34tJM7dTRcGgnOwHS5Oku-IR-mJMD2rknjMn5ifr-z-uEvynMMBwaGEYfdhs3XXQ4pKXMw2wO2GP8RD72doj4-e09I4833x-ufxR397c_r6_uCpCVSIWVDEC0vdS67q1uGt30KHpZWVR1uwar0AJIpjk0Vc9l1UDXNYrLGhRXtZJn5NsyNy_9nHOTGV0EHAY7od9Hky06u2vRZqlapBB8jAF7swtutGE2nJkDcLM1C3BzAG6YMBl4tn19S9ivR-z-md4JZ8HlIsB854vDYCI4zCw7FxCS6bz7f8JfAaSXFA</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Bańkowski, Krzysztof</creator><creator>Witkowska, Ewa</creator><creator>Michalak, Olga M.</creator><creator>Sidoryk, Katarzyna</creator><creator>Szymanek, Ewa</creator><creator>Antkowiak, Bożena</creator><creator>Paluch, Małgorzata</creator><creator>Filip, Katarzyna E.</creator><creator>Cebrat, Marek</creator><creator>Setner, Bartosz</creator><creator>Szewczuk, Zbigniew</creator><creator>Stefanowicz, Piotr</creator><creator>Cmoch, Piotr</creator><creator>Izdebski, Jan</creator><general>Elsevier Masson SAS</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>20130501</creationdate><title>Synthesis, biological activity and resistance to proteolytic digestion of new cyclic dermorphin/deltorphin analogues</title><author>Bańkowski, Krzysztof ; Witkowska, Ewa ; Michalak, Olga M. ; Sidoryk, Katarzyna ; Szymanek, Ewa ; Antkowiak, Bożena ; Paluch, Małgorzata ; Filip, Katarzyna E. ; Cebrat, Marek ; Setner, Bartosz ; Szewczuk, Zbigniew ; Stefanowicz, Piotr ; Cmoch, Piotr ; Izdebski, Jan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-a30cc29f3557fa58858fe2f36ae479bca4eacc3051c86f1368cdd84137c414743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Analgesics, Opioid - chemical synthesis</topic><topic>Analgesics, Opioid - chemistry</topic><topic>Analgesics, Opioid - pharmacology</topic><topic>Animals</topic><topic>Antinociceptive effect</topic><topic>Chymotrypsin - metabolism</topic><topic>Cyclic opioid peptides</topic><topic>Dermorphin/deltorphin analogues</topic><topic>Hot Temperature - adverse effects</topic><topic>Hydrolysis</topic><topic>Hyperalgesia - etiology</topic><topic>Hyperalgesia - physiopathology</topic><topic>Hyperalgesia - prevention & control</topic><topic>Indoles</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Models, Chemical</topic><topic>Molecular Structure</topic><topic>Oligopeptides - chemical synthesis</topic><topic>Oligopeptides - chemistry</topic><topic>Oligopeptides - pharmacology</topic><topic>Opioid Peptides - chemical synthesis</topic><topic>Opioid Peptides - chemistry</topic><topic>Opioid Peptides - pharmacology</topic><topic>Pepsin A - metabolism</topic><topic>Peptide synthesis</topic><topic>Proteolysis</topic><topic>Spectrometry, Mass, Electrospray Ionization</topic><topic>Stability to proteolytic enzymes</topic><topic>Styrenes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bańkowski, Krzysztof</creatorcontrib><creatorcontrib>Witkowska, Ewa</creatorcontrib><creatorcontrib>Michalak, Olga M.</creatorcontrib><creatorcontrib>Sidoryk, Katarzyna</creatorcontrib><creatorcontrib>Szymanek, Ewa</creatorcontrib><creatorcontrib>Antkowiak, Bożena</creatorcontrib><creatorcontrib>Paluch, Małgorzata</creatorcontrib><creatorcontrib>Filip, Katarzyna E.</creatorcontrib><creatorcontrib>Cebrat, Marek</creatorcontrib><creatorcontrib>Setner, Bartosz</creatorcontrib><creatorcontrib>Szewczuk, Zbigniew</creatorcontrib><creatorcontrib>Stefanowicz, Piotr</creatorcontrib><creatorcontrib>Cmoch, Piotr</creatorcontrib><creatorcontrib>Izdebski, Jan</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>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bańkowski, Krzysztof</au><au>Witkowska, Ewa</au><au>Michalak, Olga M.</au><au>Sidoryk, Katarzyna</au><au>Szymanek, Ewa</au><au>Antkowiak, Bożena</au><au>Paluch, Małgorzata</au><au>Filip, Katarzyna E.</au><au>Cebrat, Marek</au><au>Setner, Bartosz</au><au>Szewczuk, Zbigniew</au><au>Stefanowicz, Piotr</au><au>Cmoch, Piotr</au><au>Izdebski, Jan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, biological activity and resistance to proteolytic digestion of new cyclic dermorphin/deltorphin analogues</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>63</volume><spage>457</spage><epage>467</epage><pages>457-467</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>A series of novel cyclic ureidopeptides, analogues of dermorphine/deltorphine tetrapeptide, were synthesized by solid phase peptide synthesis and/or in solution. The antinociceptive activity of N-substituted amides 1–10 was evaluated using hot-plate and tail-flick tests. Analogue 1 showed significant, stronger than morphine, antinociceptive effect after systemic applications. All analogues were also tested for their in vitro resistance to proteolysis by means of mass spectroscopy and it was found that all substituted amides 1–10 showed full stability during incubation with large excess of chymotrypsin and pepsin. Compound 1 is a lead molecule for further evaluation.
[Display omitted]
► Novel cyclic ureidopeptides analogues of dermorphin/deltorphin were synthesized. ► Their in vivo antinociceptive activity and resistance to proteolysis were evaluated. ► N-substituted amides with D-amino acid showed extremely high proteolytic stability. ► Analogue 1 showed significant antinociceptive effect after systemic applications.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>23523659</pmid><doi>10.1016/j.ejmech.2013.02.019</doi><tpages>11</tpages></addata></record> |
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| subjects | Analgesics, Opioid - chemical synthesis Analgesics, Opioid - chemistry Analgesics, Opioid - pharmacology Animals Antinociceptive effect Chymotrypsin - metabolism Cyclic opioid peptides Dermorphin/deltorphin analogues Hot Temperature - adverse effects Hydrolysis Hyperalgesia - etiology Hyperalgesia - physiopathology Hyperalgesia - prevention & control Indoles Male Mice Mice, Inbred BALB C Models, Chemical Molecular Structure Oligopeptides - chemical synthesis Oligopeptides - chemistry Oligopeptides - pharmacology Opioid Peptides - chemical synthesis Opioid Peptides - chemistry Opioid Peptides - pharmacology Pepsin A - metabolism Peptide synthesis Proteolysis Spectrometry, Mass, Electrospray Ionization Stability to proteolytic enzymes Styrenes |
| title | Synthesis, biological activity and resistance to proteolytic digestion of new cyclic dermorphin/deltorphin analogues |
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