N-Methylated analogs of Ac[Nle28,31]CCK(26-33): synthesis, activity, and receptor selectivity
A series of singularly N-methylated analogs of Ac[Nle28,31]CCK(26-33) were synthesized by the solid-phase methodology, and their biological activity was tested in three different in vitro bioassays. The bioassays employed were the guinea pig gallbladder (GPGB), stomach (GPS), and ileum (GPI). All N-...
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| Veröffentlicht in: | Journal of medicinal chemistry 1992-07, Vol.35 (15), p.2806-2811 |
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| container_title | Journal of medicinal chemistry |
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| creator | Ron, D Gilon, C Hanani, M Vromen, A Selinger, Z Chorev, M |
| description | A series of singularly N-methylated analogs of Ac[Nle28,31]CCK(26-33) were synthesized by the solid-phase methodology, and their biological activity was tested in three different in vitro bioassays. The bioassays employed were the guinea pig gallbladder (GPGB), stomach (GPS), and ileum (GPI). All N-methyl analogs were agonists in all three bioassays. N-Methylation at either N- or C-terminals did not affect potency and selectivity, whereas N-methylation of internal residues [Nle28,(N-Me)Nle31]- and [Nle28,31,(N-Me)Trp30]CCK(26-33) in the sequence resulted in analogs which were 10-fold less potent than Ac[Nle28,31]CCK(26-33) in all three preparations. Different rank orders of potencies observed for [Nle28,31,Sar29]- and [Nle28,31,(N-Me)Asp32]CCK(26-33) analogs correspond to increased selectivity to either GPGB or GPS, respectively. We propose that systematic N-methylation of single amide bonds in a bioactive peptide should be conducted as an additional routine to probe structure-activity relationships. |
| doi_str_mv | 10.1021/jm00093a013 |
| format | Article |
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The bioassays employed were the guinea pig gallbladder (GPGB), stomach (GPS), and ileum (GPI). All N-methyl analogs were agonists in all three bioassays. N-Methylation at either N- or C-terminals did not affect potency and selectivity, whereas N-methylation of internal residues [Nle28,(N-Me)Nle31]- and [Nle28,31,(N-Me)Trp30]CCK(26-33) in the sequence resulted in analogs which were 10-fold less potent than Ac[Nle28,31]CCK(26-33) in all three preparations. Different rank orders of potencies observed for [Nle28,31,Sar29]- and [Nle28,31,(N-Me)Asp32]CCK(26-33) analogs correspond to increased selectivity to either GPGB or GPS, respectively. We propose that systematic N-methylation of single amide bonds in a bioactive peptide should be conducted as an additional routine to probe structure-activity relationships.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00093a013</identifier><identifier>PMID: 1495013</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Amino Acid Sequence ; Animals ; Chemistry ; Exact sciences and technology ; Gallbladder - drug effects ; Guinea Pigs ; Ileum - drug effects ; In Vitro Techniques ; Male ; Methylation ; Molecular Sequence Data ; Organic chemistry ; Peptide Fragments - chemical synthesis ; Peptide Fragments - metabolism ; Peptide Fragments - pharmacology ; Peptides ; Preparations and properties ; Receptors, Cholecystokinin - metabolism ; Sincalide - analogs & derivatives ; Sincalide - chemical synthesis ; Sincalide - metabolism ; Sincalide - pharmacology ; Stomach - drug effects</subject><ispartof>Journal of medicinal chemistry, 1992-07, Vol.35 (15), p.2806-2811</ispartof><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-e2e6bc51be0eabc446eea355d4afa8d4ab4ca2347ed8f6fade1393b743ce1b093</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/jm00093a013$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00093a013$$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=5431718$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1495013$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ron, D</creatorcontrib><creatorcontrib>Gilon, C</creatorcontrib><creatorcontrib>Hanani, M</creatorcontrib><creatorcontrib>Vromen, A</creatorcontrib><creatorcontrib>Selinger, Z</creatorcontrib><creatorcontrib>Chorev, M</creatorcontrib><title>N-Methylated analogs of Ac[Nle28,31]CCK(26-33): synthesis, activity, and receptor selectivity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of singularly N-methylated analogs of Ac[Nle28,31]CCK(26-33) were synthesized by the solid-phase methodology, and their biological activity was tested in three different in vitro bioassays. The bioassays employed were the guinea pig gallbladder (GPGB), stomach (GPS), and ileum (GPI). All N-methyl analogs were agonists in all three bioassays. N-Methylation at either N- or C-terminals did not affect potency and selectivity, whereas N-methylation of internal residues [Nle28,(N-Me)Nle31]- and [Nle28,31,(N-Me)Trp30]CCK(26-33) in the sequence resulted in analogs which were 10-fold less potent than Ac[Nle28,31]CCK(26-33) in all three preparations. Different rank orders of potencies observed for [Nle28,31,Sar29]- and [Nle28,31,(N-Me)Asp32]CCK(26-33) analogs correspond to increased selectivity to either GPGB or GPS, respectively. We propose that systematic N-methylation of single amide bonds in a bioactive peptide should be conducted as an additional routine to probe structure-activity relationships.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Chemistry</subject><subject>Exact sciences and technology</subject><subject>Gallbladder - drug effects</subject><subject>Guinea Pigs</subject><subject>Ileum - drug effects</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Methylation</subject><subject>Molecular Sequence Data</subject><subject>Organic chemistry</subject><subject>Peptide Fragments - chemical synthesis</subject><subject>Peptide Fragments - metabolism</subject><subject>Peptide Fragments - pharmacology</subject><subject>Peptides</subject><subject>Preparations and properties</subject><subject>Receptors, Cholecystokinin - metabolism</subject><subject>Sincalide - analogs & derivatives</subject><subject>Sincalide - chemical synthesis</subject><subject>Sincalide - metabolism</subject><subject>Sincalide - pharmacology</subject><subject>Stomach - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0d9PFDEQB_CGaPBAnnw22QeDGFnptN0f5xu5KBJPJAGfDGlmu7Oyx97u0ekZ7r-3ZC_ogy9tk-8n0-lUiFcgP4BUcLJYSimnGiXoHTGBTMnUlNI8ExMplUpVrvQLsce8iEyD0rtiF8w0i3wibi7SbxRuNx0GqhPssRt-cTI0yan7edGRKo813MxmX49Unmr97mPCmz7cErd8nKAL7e82bOKprxNPjlZh8AlTR9vkpXjeYMd0sN33xY_Pn65nX9L597Pz2ek8RQ1ZSElRXrkMKpKElTMmJ0KdZbXBBsu4Vsah0qagumzyBmsCPdVVYbQjqOLT98XhWHflh_s1cbDLlh11HfY0rNkWWk5lrsoI34_Q-YHZU2NXvl2i31iQ9nGY9p9hRv16W3ZdLan-a8fpxfzNNkd22DUee9fyE8uMhgIeL01H1nKgh6cY_Z3NC11k9vryys6hmBdXZ6WF6N-OHh3bxbD28Vf4vw3-AS5ilhY</recordid><startdate>19920724</startdate><enddate>19920724</enddate><creator>Ron, D</creator><creator>Gilon, C</creator><creator>Hanani, M</creator><creator>Vromen, A</creator><creator>Selinger, Z</creator><creator>Chorev, M</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>19920724</creationdate><title>N-Methylated analogs of Ac[Nle28,31]CCK(26-33): synthesis, activity, and receptor selectivity</title><author>Ron, D ; Gilon, C ; Hanani, M ; Vromen, A ; Selinger, Z ; Chorev, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-e2e6bc51be0eabc446eea355d4afa8d4ab4ca2347ed8f6fade1393b743ce1b093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Chemistry</topic><topic>Exact sciences and technology</topic><topic>Gallbladder - drug effects</topic><topic>Guinea Pigs</topic><topic>Ileum - drug effects</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Methylation</topic><topic>Molecular Sequence Data</topic><topic>Organic chemistry</topic><topic>Peptide Fragments - chemical synthesis</topic><topic>Peptide Fragments - metabolism</topic><topic>Peptide Fragments - pharmacology</topic><topic>Peptides</topic><topic>Preparations and properties</topic><topic>Receptors, Cholecystokinin - metabolism</topic><topic>Sincalide - analogs & derivatives</topic><topic>Sincalide - chemical synthesis</topic><topic>Sincalide - metabolism</topic><topic>Sincalide - pharmacology</topic><topic>Stomach - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ron, D</creatorcontrib><creatorcontrib>Gilon, C</creatorcontrib><creatorcontrib>Hanani, M</creatorcontrib><creatorcontrib>Vromen, A</creatorcontrib><creatorcontrib>Selinger, Z</creatorcontrib><creatorcontrib>Chorev, M</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>Ron, D</au><au>Gilon, C</au><au>Hanani, M</au><au>Vromen, A</au><au>Selinger, Z</au><au>Chorev, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>N-Methylated analogs of Ac[Nle28,31]CCK(26-33): synthesis, activity, and receptor selectivity</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1992-07-24</date><risdate>1992</risdate><volume>35</volume><issue>15</issue><spage>2806</spage><epage>2811</epage><pages>2806-2811</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of singularly N-methylated analogs of Ac[Nle28,31]CCK(26-33) were synthesized by the solid-phase methodology, and their biological activity was tested in three different in vitro bioassays. The bioassays employed were the guinea pig gallbladder (GPGB), stomach (GPS), and ileum (GPI). All N-methyl analogs were agonists in all three bioassays. N-Methylation at either N- or C-terminals did not affect potency and selectivity, whereas N-methylation of internal residues [Nle28,(N-Me)Nle31]- and [Nle28,31,(N-Me)Trp30]CCK(26-33) in the sequence resulted in analogs which were 10-fold less potent than Ac[Nle28,31]CCK(26-33) in all three preparations. Different rank orders of potencies observed for [Nle28,31,Sar29]- and [Nle28,31,(N-Me)Asp32]CCK(26-33) analogs correspond to increased selectivity to either GPGB or GPS, respectively. We propose that systematic N-methylation of single amide bonds in a bioactive peptide should be conducted as an additional routine to probe structure-activity relationships.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>1495013</pmid><doi>10.1021/jm00093a013</doi><tpages>6</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1992-07, Vol.35 (15), p.2806-2811 |
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| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Amino Acid Sequence Animals Chemistry Exact sciences and technology Gallbladder - drug effects Guinea Pigs Ileum - drug effects In Vitro Techniques Male Methylation Molecular Sequence Data Organic chemistry Peptide Fragments - chemical synthesis Peptide Fragments - metabolism Peptide Fragments - pharmacology Peptides Preparations and properties Receptors, Cholecystokinin - metabolism Sincalide - analogs & derivatives Sincalide - chemical synthesis Sincalide - metabolism Sincalide - pharmacology Stomach - drug effects |
| title | N-Methylated analogs of Ac[Nle28,31]CCK(26-33): synthesis, activity, and receptor selectivity |
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