Influence of Lipophilicity on the Biological Activity of Cyclic Pseudopeptide NK-2 Receptor Antagonists
A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been car...
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| Veröffentlicht in: | Journal of medicinal chemistry 1994-10, Vol.37 (21), p.3630-3638 |
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| container_title | Journal of medicinal chemistry |
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| creator | Quartara, Laura Fabbri, Gaetano Ricci, Renzo Patacchini, Riccardo Pestellini, Vittorio Maggi, Carlo Alberto Pavone, Vincenzo Giachetti, Antonio Arcamone, Federico |
| description | A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid phase with either Fmoc or Boc strategy. The antagonist potency on NK-2 receptors in the hamster isolated trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases with Xaa lipophilicity; cyclo(Leu psi[CH2NH]Cha-Gln-Trp-Phe-beta Ala) and cyclo(Leu psi[CH2NH]Asp(NHBzl)-Gln-Trp-Phe-beta Ala) resulted in being the two most active antagonists (pA2 = 9.06 and 9.26 on HT, respectively). A significant linear correlation was found between pA2 values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biological activities of cyclic hexapeptides containing or not containing the aminomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor. |
| doi_str_mv | 10.1021/jm00047a020 |
| format | Article |
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Syntheses have been carried out in solid phase with either Fmoc or Boc strategy. The antagonist potency on NK-2 receptors in the hamster isolated trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases with Xaa lipophilicity; cyclo(Leu psi[CH2NH]Cha-Gln-Trp-Phe-beta Ala) and cyclo(Leu psi[CH2NH]Asp(NHBzl)-Gln-Trp-Phe-beta Ala) resulted in being the two most active antagonists (pA2 = 9.06 and 9.26 on HT, respectively). A significant linear correlation was found between pA2 values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biological activities of cyclic hexapeptides containing or not containing the aminomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00047a020</identifier><identifier>PMID: 7932590</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Alkylation ; Amino Acid Sequence ; Animals ; Biological Assay ; Chemistry ; Chromatography, High Pressure Liquid ; Cricetinae ; Cyclization ; Exact sciences and technology ; Lipid Metabolism ; Male ; Mesocricetus ; Molecular Sequence Data ; Organic chemistry ; Peptides ; Peptides - chemistry ; Peptides - pharmacology ; Peptides, Cyclic - chemical synthesis ; Peptides, Cyclic - pharmacology ; Preparations and properties ; Pulmonary Artery - metabolism ; Rabbits ; Receptors, Neurokinin-2 - antagonists & inhibitors ; Structure-Activity Relationship ; Trachea - metabolism</subject><ispartof>Journal of medicinal chemistry, 1994-10, Vol.37 (21), p.3630-3638</ispartof><rights>1995 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a329t-7f1642e9a38c048b8e7610fa96eb7d86ea4a8930fbbf3507b9d8171d55ff83f3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00047a020$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00047a020$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,2752,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3308057$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7932590$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Quartara, Laura</creatorcontrib><creatorcontrib>Fabbri, Gaetano</creatorcontrib><creatorcontrib>Ricci, Renzo</creatorcontrib><creatorcontrib>Patacchini, Riccardo</creatorcontrib><creatorcontrib>Pestellini, Vittorio</creatorcontrib><creatorcontrib>Maggi, Carlo Alberto</creatorcontrib><creatorcontrib>Pavone, Vincenzo</creatorcontrib><creatorcontrib>Giachetti, Antonio</creatorcontrib><creatorcontrib>Arcamone, Federico</creatorcontrib><title>Influence of Lipophilicity on the Biological Activity of Cyclic Pseudopeptide NK-2 Receptor Antagonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid phase with either Fmoc or Boc strategy. The antagonist potency on NK-2 receptors in the hamster isolated trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases with Xaa lipophilicity; cyclo(Leu psi[CH2NH]Cha-Gln-Trp-Phe-beta Ala) and cyclo(Leu psi[CH2NH]Asp(NHBzl)-Gln-Trp-Phe-beta Ala) resulted in being the two most active antagonists (pA2 = 9.06 and 9.26 on HT, respectively). A significant linear correlation was found between pA2 values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biological activities of cyclic hexapeptides containing or not containing the aminomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor.</description><subject>Alkylation</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Biological Assay</subject><subject>Chemistry</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cricetinae</subject><subject>Cyclization</subject><subject>Exact sciences and technology</subject><subject>Lipid Metabolism</subject><subject>Male</subject><subject>Mesocricetus</subject><subject>Molecular Sequence Data</subject><subject>Organic chemistry</subject><subject>Peptides</subject><subject>Peptides - chemistry</subject><subject>Peptides - pharmacology</subject><subject>Peptides, Cyclic - chemical synthesis</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Preparations and properties</subject><subject>Pulmonary Artery - metabolism</subject><subject>Rabbits</subject><subject>Receptors, Neurokinin-2 - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Trachea - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0M-LEzEUB_AgylpXT56FHEQPMvqSzOTHsRZ1F8u6aO8hk0m6qdPJbDIj9r832lI8CJLDI3w_PB5fhJ4TeEuAkne7PQDUwgCFB2hBGgpVLaF-iBYAlFaUU_YYPcl5VxgjlF2gC6EYbRQs0PZ68P3sButw9HgdxjjehT7YMB1wHPB05_D7EPu4Ddb0eGmn8ONP5PHqYIvDt9nNXRzdOIXO4ZvPFcVfnS3fmPBymMw2DiFP-Sl65E2f3bPTvESbjx82q6tq_eXT9Wq5rgyjaqqEJ7ymThkmLdSylU5wAt4o7lrRSe5MbaRi4NvWswZEqzpJBOmaxnvJPLtEr45rxxTvZ5cnvQ_Zur43g4tz1oKXJ0n9X0i4JKpRtMA3R2hTzDk5r8cU9iYdNAH9u379V_1Fvzitndu968721HfJX55yk0uhPpnBhnxmjIGERhRWHVmpzv08xyZ911ww0ejN7Td9RZUUXNb6pvjXR29s1rs4p6F0_M8DfwFkt6es</recordid><startdate>19941001</startdate><enddate>19941001</enddate><creator>Quartara, Laura</creator><creator>Fabbri, Gaetano</creator><creator>Ricci, Renzo</creator><creator>Patacchini, Riccardo</creator><creator>Pestellini, Vittorio</creator><creator>Maggi, Carlo Alberto</creator><creator>Pavone, Vincenzo</creator><creator>Giachetti, Antonio</creator><creator>Arcamone, Federico</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>7TK</scope><scope>7X8</scope></search><sort><creationdate>19941001</creationdate><title>Influence of Lipophilicity on the Biological Activity of Cyclic Pseudopeptide NK-2 Receptor Antagonists</title><author>Quartara, Laura ; Fabbri, Gaetano ; Ricci, Renzo ; Patacchini, Riccardo ; Pestellini, Vittorio ; Maggi, Carlo Alberto ; Pavone, Vincenzo ; Giachetti, Antonio ; Arcamone, Federico</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a329t-7f1642e9a38c048b8e7610fa96eb7d86ea4a8930fbbf3507b9d8171d55ff83f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Alkylation</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Biological Assay</topic><topic>Chemistry</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Cricetinae</topic><topic>Cyclization</topic><topic>Exact sciences and technology</topic><topic>Lipid Metabolism</topic><topic>Male</topic><topic>Mesocricetus</topic><topic>Molecular Sequence Data</topic><topic>Organic chemistry</topic><topic>Peptides</topic><topic>Peptides - chemistry</topic><topic>Peptides - pharmacology</topic><topic>Peptides, Cyclic - chemical synthesis</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Preparations and properties</topic><topic>Pulmonary Artery - metabolism</topic><topic>Rabbits</topic><topic>Receptors, Neurokinin-2 - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Trachea - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Quartara, Laura</creatorcontrib><creatorcontrib>Fabbri, Gaetano</creatorcontrib><creatorcontrib>Ricci, Renzo</creatorcontrib><creatorcontrib>Patacchini, Riccardo</creatorcontrib><creatorcontrib>Pestellini, Vittorio</creatorcontrib><creatorcontrib>Maggi, Carlo Alberto</creatorcontrib><creatorcontrib>Pavone, Vincenzo</creatorcontrib><creatorcontrib>Giachetti, Antonio</creatorcontrib><creatorcontrib>Arcamone, Federico</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>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Quartara, Laura</au><au>Fabbri, Gaetano</au><au>Ricci, Renzo</au><au>Patacchini, Riccardo</au><au>Pestellini, Vittorio</au><au>Maggi, Carlo Alberto</au><au>Pavone, Vincenzo</au><au>Giachetti, Antonio</au><au>Arcamone, Federico</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Influence of Lipophilicity on the Biological Activity of Cyclic Pseudopeptide NK-2 Receptor Antagonists</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1994-10-01</date><risdate>1994</risdate><volume>37</volume><issue>21</issue><spage>3630</spage><epage>3638</epage><pages>3630-3638</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid phase with either Fmoc or Boc strategy. The antagonist potency on NK-2 receptors in the hamster isolated trachea (HT) and the rabbit isolated pulmonary artery (RPA) bioassays increases with Xaa lipophilicity; cyclo(Leu psi[CH2NH]Cha-Gln-Trp-Phe-beta Ala) and cyclo(Leu psi[CH2NH]Asp(NHBzl)-Gln-Trp-Phe-beta Ala) resulted in being the two most active antagonists (pA2 = 9.06 and 9.26 on HT, respectively). A significant linear correlation was found between pA2 values determined in HT and RPA bioassays and capacity factors measured in reversed phase HPLC. The comparison between the biological activities of cyclic hexapeptides containing or not containing the aminomethylene moiety proved the crucial role of the pseudopeptide bond for determining high antagonist potency at the NK-2 receptor.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>7932590</pmid><doi>10.1021/jm00047a020</doi><tpages>9</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1994-10, Vol.37 (21), p.3630-3638 |
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| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Alkylation Amino Acid Sequence Animals Biological Assay Chemistry Chromatography, High Pressure Liquid Cricetinae Cyclization Exact sciences and technology Lipid Metabolism Male Mesocricetus Molecular Sequence Data Organic chemistry Peptides Peptides - chemistry Peptides - pharmacology Peptides, Cyclic - chemical synthesis Peptides, Cyclic - pharmacology Preparations and properties Pulmonary Artery - metabolism Rabbits Receptors, Neurokinin-2 - antagonists & inhibitors Structure-Activity Relationship Trachea - metabolism |
| title | Influence of Lipophilicity on the Biological Activity of Cyclic Pseudopeptide NK-2 Receptor Antagonists |
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