Anthranilic acid derivatives : A new class of non-peptide CCK1 receptor antagonists
Having successfully obtained new CCK(1) ligands holding appropriate groups on the anthranilic acid dimer used as molecular scaffold we were interested in increasing their micromolar affinity for the CCK(1) receptors by modifying the spatial relationship of the main pharmacophoric groups. Since, we h...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2003-03, Vol.11 (5), p.741-751 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | VARNAVAS, Antonio LASSIANI, Lucia VALENTA, Valentina BERTI, Federico MENNUNI, Laura MAKOVEC, Francesco |
| description | Having successfully obtained new CCK(1) ligands holding appropriate groups on the anthranilic acid dimer used as molecular scaffold we were interested in increasing their micromolar affinity for the CCK(1) receptors by modifying the spatial relationship of the main pharmacophoric groups. Since, we have proposed simplified analogues reducing the anthranilic acid dimer to a monomer. In this stage of our research program we have prepared and tested on CCK receptors a series of N-substituted anthranilic acid derivatives keeping a Phe residue at the C-terminal site. The indole-2-carbonyl group imparts the best CCK(1) receptor binding affinity (compound 1: IC(50)=197.5 nM) while a sharp decrease in binding affinity is observed for the other indole containing derivatives. Moreover, in order to support the different binding behaviour observed for the synthesized compounds, a conformational investigation was carried out. Finally, on the basis of the main pharmacophoric groups of the obtained new lead compound (1) (coded VL-0395) a receptor binding hypothesis has been provided. |
| doi_str_mv | 10.1016/S0968-0896(02)00475-3 |
| format | Article |
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Since, we have proposed simplified analogues reducing the anthranilic acid dimer to a monomer. In this stage of our research program we have prepared and tested on CCK receptors a series of N-substituted anthranilic acid derivatives keeping a Phe residue at the C-terminal site. The indole-2-carbonyl group imparts the best CCK(1) receptor binding affinity (compound 1: IC(50)=197.5 nM) while a sharp decrease in binding affinity is observed for the other indole containing derivatives. Moreover, in order to support the different binding behaviour observed for the synthesized compounds, a conformational investigation was carried out. Finally, on the basis of the main pharmacophoric groups of the obtained new lead compound (1) (coded VL-0395) a receptor binding hypothesis has been provided.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/S0968-0896(02)00475-3</identifier><identifier>PMID: 12538004</identifier><language>eng</language><publisher>Oxford: Elsevier Science</publisher><subject>Animals ; Biological and medical sciences ; Cerebral Cortex - drug effects ; Cerebral Cortex - metabolism ; Chromatography, Thin Layer ; Guinea Pigs ; Indicators and Reagents ; Medical sciences ; Models, Molecular ; Molecular Conformation ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; ortho-Aminobenzoates - chemical synthesis ; ortho-Aminobenzoates - pharmacology ; Pancreas - drug effects ; Pancreas - metabolism ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. Drug treatments ; Rats ; Rats, Sprague-Dawley ; Receptor, Cholecystokinin A ; Receptors, Cholecystokinin - antagonists & inhibitors ; Receptors, Cholecystokinin - drug effects ; Receptors, Cholecystokinin - metabolism ; Spectrophotometry, Ultraviolet ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry, 2003-03, Vol.11 (5), p.741-751</ispartof><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c335t-e91e8e1f500b648583012905ab5565476e1bfb80ae6534ce09794540cafa6a3a3</citedby><cites>FETCH-LOGICAL-c335t-e91e8e1f500b648583012905ab5565476e1bfb80ae6534ce09794540cafa6a3a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17280537$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12538004$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>VARNAVAS, Antonio</creatorcontrib><creatorcontrib>LASSIANI, Lucia</creatorcontrib><creatorcontrib>VALENTA, Valentina</creatorcontrib><creatorcontrib>BERTI, Federico</creatorcontrib><creatorcontrib>MENNUNI, Laura</creatorcontrib><creatorcontrib>MAKOVEC, Francesco</creatorcontrib><title>Anthranilic acid derivatives : A new class of non-peptide CCK1 receptor antagonists</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>Having successfully obtained new CCK(1) ligands holding appropriate groups on the anthranilic acid dimer used as molecular scaffold we were interested in increasing their micromolar affinity for the CCK(1) receptors by modifying the spatial relationship of the main pharmacophoric groups. Since, we have proposed simplified analogues reducing the anthranilic acid dimer to a monomer. In this stage of our research program we have prepared and tested on CCK receptors a series of N-substituted anthranilic acid derivatives keeping a Phe residue at the C-terminal site. The indole-2-carbonyl group imparts the best CCK(1) receptor binding affinity (compound 1: IC(50)=197.5 nM) while a sharp decrease in binding affinity is observed for the other indole containing derivatives. Moreover, in order to support the different binding behaviour observed for the synthesized compounds, a conformational investigation was carried out. Finally, on the basis of the main pharmacophoric groups of the obtained new lead compound (1) (coded VL-0395) a receptor binding hypothesis has been provided.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cerebral Cortex - drug effects</subject><subject>Cerebral Cortex - metabolism</subject><subject>Chromatography, Thin Layer</subject><subject>Guinea Pigs</subject><subject>Indicators and Reagents</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>ortho-Aminobenzoates - chemical synthesis</subject><subject>ortho-Aminobenzoates - pharmacology</subject><subject>Pancreas - drug effects</subject><subject>Pancreas - metabolism</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor, Cholecystokinin A</subject><subject>Receptors, Cholecystokinin - antagonists & inhibitors</subject><subject>Receptors, Cholecystokinin - drug effects</subject><subject>Receptors, Cholecystokinin - metabolism</subject><subject>Spectrophotometry, Ultraviolet</subject><subject>Structure-Activity Relationship</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1PGzEQQC3UCkLKTyjypRU9LIzXH2tziyJoKyJxSDlbs85scbXZTe1NUP89mxCV02ik92akx9hnAdcChLlZgjO2AOvMFZTfAFSlC3nCJkIZVUjpxAc2-Y-csfOc_wBAqZw4ZWei1NKOzoQtZ93wnLCLbQwcQ1zxFaW4wyHuKPNbPuMdvfDQYs68b3jXd8WGNkNcEZ_PHwRPFMa1Txy7AX_3XcxD_sQ-NthmujjOKXu6v_s1_1EsHr__nM8WRZBSDwU5QZZEowFqo6y2EkTpQGOttdGqMiTqpraAZLRUgcBVTmkFARs0KFFO2de3u5vU_91SHvw65kBtix312-yr0lXWuXIE9RsYUp9zosZvUlxj-ucF-H1Nf6jp96k8lP5Q08vRuzw-2NZrWr1bx3wj8OUIYA7YNmPIEPM7V5UWtKzkK54Ce7o</recordid><startdate>20030306</startdate><enddate>20030306</enddate><creator>VARNAVAS, Antonio</creator><creator>LASSIANI, Lucia</creator><creator>VALENTA, Valentina</creator><creator>BERTI, Federico</creator><creator>MENNUNI, Laura</creator><creator>MAKOVEC, Francesco</creator><general>Elsevier Science</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>7X8</scope></search><sort><creationdate>20030306</creationdate><title>Anthranilic acid derivatives : A new class of non-peptide CCK1 receptor antagonists</title><author>VARNAVAS, Antonio ; LASSIANI, Lucia ; VALENTA, Valentina ; BERTI, Federico ; MENNUNI, Laura ; MAKOVEC, Francesco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c335t-e91e8e1f500b648583012905ab5565476e1bfb80ae6534ce09794540cafa6a3a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cerebral Cortex - drug effects</topic><topic>Cerebral Cortex - metabolism</topic><topic>Chromatography, Thin Layer</topic><topic>Guinea Pigs</topic><topic>Indicators and Reagents</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>ortho-Aminobenzoates - chemical synthesis</topic><topic>ortho-Aminobenzoates - pharmacology</topic><topic>Pancreas - drug effects</topic><topic>Pancreas - metabolism</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor, Cholecystokinin A</topic><topic>Receptors, Cholecystokinin - antagonists & inhibitors</topic><topic>Receptors, Cholecystokinin - drug effects</topic><topic>Receptors, Cholecystokinin - metabolism</topic><topic>Spectrophotometry, Ultraviolet</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>VARNAVAS, Antonio</creatorcontrib><creatorcontrib>LASSIANI, Lucia</creatorcontrib><creatorcontrib>VALENTA, Valentina</creatorcontrib><creatorcontrib>BERTI, Federico</creatorcontrib><creatorcontrib>MENNUNI, Laura</creatorcontrib><creatorcontrib>MAKOVEC, Francesco</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>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>VARNAVAS, Antonio</au><au>LASSIANI, Lucia</au><au>VALENTA, Valentina</au><au>BERTI, Federico</au><au>MENNUNI, Laura</au><au>MAKOVEC, Francesco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anthranilic acid derivatives : A new class of non-peptide CCK1 receptor antagonists</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2003-03-06</date><risdate>2003</risdate><volume>11</volume><issue>5</issue><spage>741</spage><epage>751</epage><pages>741-751</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>Having successfully obtained new CCK(1) ligands holding appropriate groups on the anthranilic acid dimer used as molecular scaffold we were interested in increasing their micromolar affinity for the CCK(1) receptors by modifying the spatial relationship of the main pharmacophoric groups. Since, we have proposed simplified analogues reducing the anthranilic acid dimer to a monomer. In this stage of our research program we have prepared and tested on CCK receptors a series of N-substituted anthranilic acid derivatives keeping a Phe residue at the C-terminal site. The indole-2-carbonyl group imparts the best CCK(1) receptor binding affinity (compound 1: IC(50)=197.5 nM) while a sharp decrease in binding affinity is observed for the other indole containing derivatives. Moreover, in order to support the different binding behaviour observed for the synthesized compounds, a conformational investigation was carried out. Finally, on the basis of the main pharmacophoric groups of the obtained new lead compound (1) (coded VL-0395) a receptor binding hypothesis has been provided.</abstract><cop>Oxford</cop><pub>Elsevier Science</pub><pmid>12538004</pmid><doi>10.1016/S0968-0896(02)00475-3</doi><tpages>11</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Cerebral Cortex - drug effects Cerebral Cortex - metabolism Chromatography, Thin Layer Guinea Pigs Indicators and Reagents Medical sciences Models, Molecular Molecular Conformation Neuropharmacology Neurotransmitters. Neurotransmission. Receptors ortho-Aminobenzoates - chemical synthesis ortho-Aminobenzoates - pharmacology Pancreas - drug effects Pancreas - metabolism Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Rats Rats, Sprague-Dawley Receptor, Cholecystokinin A Receptors, Cholecystokinin - antagonists & inhibitors Receptors, Cholecystokinin - drug effects Receptors, Cholecystokinin - metabolism Spectrophotometry, Ultraviolet Structure-Activity Relationship |
| title | Anthranilic acid derivatives : A new class of non-peptide CCK1 receptor antagonists |
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