Analogues of Neurohypophyseal Hormones, Oxytocin and Arginine Vasopressin, Conformationally Restricted in the N-Terminal Part of the Molecule
It is generally accepted that the conformation of the N-terminal part of neurohypophyseal hormones analogues is important for their pharmacological activity. In this work, we decided to investigate how the substitution of positions 2 and 3 with the ethylene-bridged dipeptide would alter the pharmaco...
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| Veröffentlicht in: | Journal of medicinal chemistry 2006-03, Vol.49 (6), p.2016-2021 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 49 |
| creator | Kowalczyk, Wioleta Prahl, Adam Derdowska, Izabela Sobolewski, Dariusz Olejnik, Jadwiga Zabrocki, Janusz Borovicková, Lenka Slaninová, Jiřina Lammek, Bernard |
| description | It is generally accepted that the conformation of the N-terminal part of neurohypophyseal hormones analogues is important for their pharmacological activity. In this work, we decided to investigate how the substitution of positions 2 and 3 with the ethylene-bridged dipeptide would alter the pharmacological properties of OT, [Mpa]OT, and [Cpa1]OT (OT = oxytocin; Mpa = 3-mercaptopropionic acid; Cpa = 1-mercaptocyclohexaneacetic acid) and to investigate how a bulky 3,3-diphenyl-l-alanine residue incorporated in position 2 of AVP, [Mpa1]AVP, and [Cpa1]AVP (AVP = arginine vasopressin) would change the pharmacological profile of the compounds. The next analogues, [Val4]AVP, [Mpa1,Val4]AVP, and [Cpa1,Val4]AVP, had N-benzyl-l-alanine introduced at position 3. The last peptide was designed by Cys1 substitution in AVP by its sterically restricted bulky counterpart, α-hydroxymethylcysteine. All the peptides were tested for their in vitro uterotonic, pressor, and antidiuretic activities in the rat. The results of these assays showed that the reduction of conformational freedom of the N-terminal part of the molecule had a significant impact on pharmacological activities. |
| doi_str_mv | 10.1021/jm058038f |
| format | Article |
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In this work, we decided to investigate how the substitution of positions 2 and 3 with the ethylene-bridged dipeptide would alter the pharmacological properties of OT, [Mpa]OT, and [Cpa1]OT (OT = oxytocin; Mpa = 3-mercaptopropionic acid; Cpa = 1-mercaptocyclohexaneacetic acid) and to investigate how a bulky 3,3-diphenyl-l-alanine residue incorporated in position 2 of AVP, [Mpa1]AVP, and [Cpa1]AVP (AVP = arginine vasopressin) would change the pharmacological profile of the compounds. The next analogues, [Val4]AVP, [Mpa1,Val4]AVP, and [Cpa1,Val4]AVP, had N-benzyl-l-alanine introduced at position 3. The last peptide was designed by Cys1 substitution in AVP by its sterically restricted bulky counterpart, α-hydroxymethylcysteine. All the peptides were tested for their in vitro uterotonic, pressor, and antidiuretic activities in the rat. The results of these assays showed that the reduction of conformational freedom of the N-terminal part of the molecule had a significant impact on pharmacological activities.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm058038f</identifier><identifier>PMID: 16539389</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>3-Mercaptopropionic Acid - chemistry ; Animals ; Antidiuretic Agents - chemical synthesis ; Antidiuretic Agents - pharmacology ; Arginine Vasopressin - analogs & derivatives ; Arginine Vasopressin - chemical synthesis ; Arginine Vasopressin - pharmacology ; Biological and medical sciences ; Dipeptides - chemical synthesis ; Dipeptides - pharmacology ; Female ; Hormones. Endocrine system ; Male ; Medical sciences ; Molecular Conformation ; Oxytocin - analogs & derivatives ; Oxytocin - chemical synthesis ; Oxytocin - pharmacology ; Pharmacology. Drug treatments ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; Uterine Contraction - drug effects ; Vasoconstrictor Agents - chemical synthesis ; Vasoconstrictor Agents - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2006-03, Vol.49 (6), p.2016-2021</ispartof><rights>Copyright © 2006 American Chemical Society</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-2e19988838ccd88b33dfcb952f8658b8e3934ee01b8e24d15afbf6bde8354a153</citedby><cites>FETCH-LOGICAL-a381t-2e19988838ccd88b33dfcb952f8658b8e3934ee01b8e24d15afbf6bde8354a153</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/jm058038f$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm058038f$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17650375$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16539389$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kowalczyk, Wioleta</creatorcontrib><creatorcontrib>Prahl, Adam</creatorcontrib><creatorcontrib>Derdowska, Izabela</creatorcontrib><creatorcontrib>Sobolewski, Dariusz</creatorcontrib><creatorcontrib>Olejnik, Jadwiga</creatorcontrib><creatorcontrib>Zabrocki, Janusz</creatorcontrib><creatorcontrib>Borovicková, Lenka</creatorcontrib><creatorcontrib>Slaninová, Jiřina</creatorcontrib><creatorcontrib>Lammek, Bernard</creatorcontrib><title>Analogues of Neurohypophyseal Hormones, Oxytocin and Arginine Vasopressin, Conformationally Restricted in the N-Terminal Part of the Molecule</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>It is generally accepted that the conformation of the N-terminal part of neurohypophyseal hormones analogues is important for their pharmacological activity. In this work, we decided to investigate how the substitution of positions 2 and 3 with the ethylene-bridged dipeptide would alter the pharmacological properties of OT, [Mpa]OT, and [Cpa1]OT (OT = oxytocin; Mpa = 3-mercaptopropionic acid; Cpa = 1-mercaptocyclohexaneacetic acid) and to investigate how a bulky 3,3-diphenyl-l-alanine residue incorporated in position 2 of AVP, [Mpa1]AVP, and [Cpa1]AVP (AVP = arginine vasopressin) would change the pharmacological profile of the compounds. The next analogues, [Val4]AVP, [Mpa1,Val4]AVP, and [Cpa1,Val4]AVP, had N-benzyl-l-alanine introduced at position 3. The last peptide was designed by Cys1 substitution in AVP by its sterically restricted bulky counterpart, α-hydroxymethylcysteine. All the peptides were tested for their in vitro uterotonic, pressor, and antidiuretic activities in the rat. The results of these assays showed that the reduction of conformational freedom of the N-terminal part of the molecule had a significant impact on pharmacological activities.</description><subject>3-Mercaptopropionic Acid - chemistry</subject><subject>Animals</subject><subject>Antidiuretic Agents - chemical synthesis</subject><subject>Antidiuretic Agents - pharmacology</subject><subject>Arginine Vasopressin - analogs & derivatives</subject><subject>Arginine Vasopressin - chemical synthesis</subject><subject>Arginine Vasopressin - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Dipeptides - chemical synthesis</subject><subject>Dipeptides - pharmacology</subject><subject>Female</subject><subject>Hormones. Endocrine system</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Molecular Conformation</subject><subject>Oxytocin - analogs & derivatives</subject><subject>Oxytocin - chemical synthesis</subject><subject>Oxytocin - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Structure-Activity Relationship</subject><subject>Uterine Contraction - drug effects</subject><subject>Vasoconstrictor Agents - chemical synthesis</subject><subject>Vasoconstrictor Agents - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkNFu0zAUhi0EYt3gghdAvgEJaQE7jhPnsqpgYxpdBWW3luMcry6J3dmJtDwE74yrVusNVz7y-c5__vMj9I6Sz5Tk9Mu2J1wQJswLNKM8J1khSPESzQjJ8ywvc3aGzmPcEkIYzdlrdEZLzmom6hn6O3eq8w8jROwNXsIY_Gba-d1miqA6fO1D7x3ES3z3NA1eW4eVa_E8PFhnHeB7Ff0uQIzWXeKFdybxarA-iXYT_glxCFYP0OI0OGwAL7M1hN6mNl6pMOx37r9_-A702MEb9MqoLsLb43uBfn_7ul5cZ7d3V98X89tMMUGHLAda10IIJrRuhWgYa41uap4bUXLRCEjHFQCEpjIvWsqVaUzZtCAYLxTl7AJ9POjugn9Mtw-yt1FD1ykHfoyyrCpeC0YS-OkA6uBjDGDkLthehUlSIvfZy-fsE_v-KDo2PbQn8hh2Aj4cARW16kxQTtt44qqSE1bt3WUHzsYBnp77KvxJxhIg16tf8kbwm9V9tZTFSVfpKLd-DCne-B-D_wB4tamA</recordid><startdate>20060323</startdate><enddate>20060323</enddate><creator>Kowalczyk, Wioleta</creator><creator>Prahl, Adam</creator><creator>Derdowska, Izabela</creator><creator>Sobolewski, Dariusz</creator><creator>Olejnik, Jadwiga</creator><creator>Zabrocki, Janusz</creator><creator>Borovicková, Lenka</creator><creator>Slaninová, Jiřina</creator><creator>Lammek, Bernard</creator><general>American Chemical Society</general><scope>BSCLL</scope><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>7X8</scope></search><sort><creationdate>20060323</creationdate><title>Analogues of Neurohypophyseal Hormones, Oxytocin and Arginine Vasopressin, Conformationally Restricted in the N-Terminal Part of the Molecule</title><author>Kowalczyk, Wioleta ; Prahl, Adam ; Derdowska, Izabela ; Sobolewski, Dariusz ; Olejnik, Jadwiga ; Zabrocki, Janusz ; Borovicková, Lenka ; Slaninová, Jiřina ; Lammek, Bernard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-2e19988838ccd88b33dfcb952f8658b8e3934ee01b8e24d15afbf6bde8354a153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>3-Mercaptopropionic Acid - chemistry</topic><topic>Animals</topic><topic>Antidiuretic Agents - chemical synthesis</topic><topic>Antidiuretic Agents - pharmacology</topic><topic>Arginine Vasopressin - analogs & derivatives</topic><topic>Arginine Vasopressin - chemical synthesis</topic><topic>Arginine Vasopressin - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Dipeptides - chemical synthesis</topic><topic>Dipeptides - pharmacology</topic><topic>Female</topic><topic>Hormones. Endocrine system</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Molecular Conformation</topic><topic>Oxytocin - analogs & derivatives</topic><topic>Oxytocin - chemical synthesis</topic><topic>Oxytocin - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Structure-Activity Relationship</topic><topic>Uterine Contraction - drug effects</topic><topic>Vasoconstrictor Agents - chemical synthesis</topic><topic>Vasoconstrictor Agents - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kowalczyk, Wioleta</creatorcontrib><creatorcontrib>Prahl, Adam</creatorcontrib><creatorcontrib>Derdowska, Izabela</creatorcontrib><creatorcontrib>Sobolewski, Dariusz</creatorcontrib><creatorcontrib>Olejnik, Jadwiga</creatorcontrib><creatorcontrib>Zabrocki, Janusz</creatorcontrib><creatorcontrib>Borovicková, Lenka</creatorcontrib><creatorcontrib>Slaninová, Jiřina</creatorcontrib><creatorcontrib>Lammek, Bernard</creatorcontrib><collection>Istex</collection><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>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kowalczyk, Wioleta</au><au>Prahl, Adam</au><au>Derdowska, Izabela</au><au>Sobolewski, Dariusz</au><au>Olejnik, Jadwiga</au><au>Zabrocki, Janusz</au><au>Borovicková, Lenka</au><au>Slaninová, Jiřina</au><au>Lammek, Bernard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analogues of Neurohypophyseal Hormones, Oxytocin and Arginine Vasopressin, Conformationally Restricted in the N-Terminal Part of the Molecule</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2006-03-23</date><risdate>2006</risdate><volume>49</volume><issue>6</issue><spage>2016</spage><epage>2021</epage><pages>2016-2021</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>It is generally accepted that the conformation of the N-terminal part of neurohypophyseal hormones analogues is important for their pharmacological activity. In this work, we decided to investigate how the substitution of positions 2 and 3 with the ethylene-bridged dipeptide would alter the pharmacological properties of OT, [Mpa]OT, and [Cpa1]OT (OT = oxytocin; Mpa = 3-mercaptopropionic acid; Cpa = 1-mercaptocyclohexaneacetic acid) and to investigate how a bulky 3,3-diphenyl-l-alanine residue incorporated in position 2 of AVP, [Mpa1]AVP, and [Cpa1]AVP (AVP = arginine vasopressin) would change the pharmacological profile of the compounds. The next analogues, [Val4]AVP, [Mpa1,Val4]AVP, and [Cpa1,Val4]AVP, had N-benzyl-l-alanine introduced at position 3. The last peptide was designed by Cys1 substitution in AVP by its sterically restricted bulky counterpart, α-hydroxymethylcysteine. All the peptides were tested for their in vitro uterotonic, pressor, and antidiuretic activities in the rat. The results of these assays showed that the reduction of conformational freedom of the N-terminal part of the molecule had a significant impact on pharmacological activities.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16539389</pmid><doi>10.1021/jm058038f</doi><tpages>6</tpages></addata></record> |
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| subjects | 3-Mercaptopropionic Acid - chemistry Animals Antidiuretic Agents - chemical synthesis Antidiuretic Agents - pharmacology Arginine Vasopressin - analogs & derivatives Arginine Vasopressin - chemical synthesis Arginine Vasopressin - pharmacology Biological and medical sciences Dipeptides - chemical synthesis Dipeptides - pharmacology Female Hormones. Endocrine system Male Medical sciences Molecular Conformation Oxytocin - analogs & derivatives Oxytocin - chemical synthesis Oxytocin - pharmacology Pharmacology. Drug treatments Rats Rats, Wistar Structure-Activity Relationship Uterine Contraction - drug effects Vasoconstrictor Agents - chemical synthesis Vasoconstrictor Agents - pharmacology |
| title | Analogues of Neurohypophyseal Hormones, Oxytocin and Arginine Vasopressin, Conformationally Restricted in the N-Terminal Part of the Molecule |
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