Reassessing the melatonin pharmacophore—Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue
3-(Acetylaminomethyl)-2-(ethoxycarbonyl)-6-methoxy-1,3,4,5-tetrahydrobenzo[ cd]indole ( 2) is a rigid melatonin analogue that as a racemate displays about the same affinity and intrinsic activity of melatonin ( 1) in in vitro experiments. We report here the resolution of the racemate by preparative...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry 2006-05, Vol.14 (10), p.3383-3391 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3391 |
|---|---|
| container_issue | 10 |
| container_start_page | 3383 |
| container_title | Bioorganic & medicinal chemistry |
| container_volume | 14 |
| creator | Rivara, Silvia Diamantini, Giuseppe Di Giacomo, Barbara Lamba, Doriano Gatti, Giuseppe Lucini, Valeria Pannacci, Marilou Mor, Marco Spadoni, Gilberto Tarzia, Giorgio |
| description | 3-(Acetylaminomethyl)-2-(ethoxycarbonyl)-6-methoxy-1,3,4,5-tetrahydrobenzo[
cd]indole (
2) is a rigid melatonin analogue that as a racemate displays about the same affinity and intrinsic activity of melatonin (
1) in in vitro experiments. We report here the resolution of the racemate by preparative medium pressure liquid chromatography (MPLC) and the X-ray determination of the
R absolute configuration of the (−)-enantiomer. The two enantiomers were separately tested as MT
1 and MT
2 ligands, and the (+)-(
S)-
2 showed a potency comparable to that of melatonin and about three orders of magnitude greater than that of its enantiomer. The information obtained by crystallographic analysis and NMR studies about the conformational preference for
2 and by the pharmacological characterization of (
R)-
2 and (
S)-
2 was employed in a molecular modeling study, aimed at reassessing the melatonin receptor pharmacophore model for agonist compounds. Chiral enantioselective agonists reported in the literature were also included in the study. |
| doi_str_mv | 10.1016/j.bmc.2005.12.053 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_67829817</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0968089606000058</els_id><sourcerecordid>67829817</sourcerecordid><originalsourceid>FETCH-LOGICAL-c412t-dadb82d7ddf96a1fdff01f9719a0059754795e1ec7badf7dcaabe9e73d5a39483</originalsourceid><addsrcrecordid>eNqFkU2OEzEQhVsIxISBA7BB3sAqHVz957ZYjUbDjzQSEoK1VbGrE0duO9jdI2XHITgJR-IkOEpEdrByWfreq9J7RfES-Ao4dG93q_WoVxXn7QqqFW_rR8UCmq4p61rC42LBZdeXvJfdVfEspR3nvGokPC2uoGtqgAoWxa8vhClRStZv2LQlNpLDKXjr2X6LcUQd9tsQ6fePn3ce_WTDSNFqFikFN-evX_4FXdhYjY6hnuyDnQ5LlqY462mOxNCjOySblnkybAyO9Oww5smQO-4OA0Omg88StJ4M01sbs9nlnqNF2Mz0vHgyoEv04vxeF9_e3329_Vjef_7w6fbmvtQNVFNp0Kz7yghjBtkhDGYYOAxSgMQcmBRtI2RLQFqs0QzCaMQ1SRK1abGWTV9fF29OvvsYvs-UJjXapMk59BTmpDrRV7IH8V8QBIhOiDaDcAJ1DClFGtQ-2hHjQQFXx0bVTuVG1bFRBZXKjWbNq7P5vB7JXBTnCjPw-gxgyukPEb226cKJLh_aVZl7d-IoZ_ZgKaqkLXlNxkbSkzLB_uOMP6S1xfw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>17176775</pqid></control><display><type>article</type><title>Reassessing the melatonin pharmacophore—Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue</title><source>MEDLINE</source><source>Access via ScienceDirect (Elsevier)</source><creator>Rivara, Silvia ; Diamantini, Giuseppe ; Di Giacomo, Barbara ; Lamba, Doriano ; Gatti, Giuseppe ; Lucini, Valeria ; Pannacci, Marilou ; Mor, Marco ; Spadoni, Gilberto ; Tarzia, Giorgio</creator><creatorcontrib>Rivara, Silvia ; Diamantini, Giuseppe ; Di Giacomo, Barbara ; Lamba, Doriano ; Gatti, Giuseppe ; Lucini, Valeria ; Pannacci, Marilou ; Mor, Marco ; Spadoni, Gilberto ; Tarzia, Giorgio</creatorcontrib><description>3-(Acetylaminomethyl)-2-(ethoxycarbonyl)-6-methoxy-1,3,4,5-tetrahydrobenzo[
cd]indole (
2) is a rigid melatonin analogue that as a racemate displays about the same affinity and intrinsic activity of melatonin (
1) in in vitro experiments. We report here the resolution of the racemate by preparative medium pressure liquid chromatography (MPLC) and the X-ray determination of the
R absolute configuration of the (−)-enantiomer. The two enantiomers were separately tested as MT
1 and MT
2 ligands, and the (+)-(
S)-
2 showed a potency comparable to that of melatonin and about three orders of magnitude greater than that of its enantiomer. The information obtained by crystallographic analysis and NMR studies about the conformational preference for
2 and by the pharmacological characterization of (
R)-
2 and (
S)-
2 was employed in a molecular modeling study, aimed at reassessing the melatonin receptor pharmacophore model for agonist compounds. Chiral enantioselective agonists reported in the literature were also included in the study.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2005.12.053</identifier><identifier>PMID: 16431121</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>3T3 Cells ; Animals ; Binding, Competitive - drug effects ; Biological and medical sciences ; Conformational analysis ; Crystallography, X-Ray ; Enantiomeric resolution ; Magnetic Resonance Spectroscopy ; Medical sciences ; Melatonin ; Melatonin - analogs & derivatives ; Melatonin - chemistry ; Melatonin - pharmacology ; Mice ; Models, Molecular ; Molecular modeling ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. Drug treatments ; Pharmacophore model ; Receptors, Melatonin - metabolism ; Stereoisomerism ; Structure-Activity Relationship ; X-ray crystal structure</subject><ispartof>Bioorganic & medicinal chemistry, 2006-05, Vol.14 (10), p.3383-3391</ispartof><rights>2006 Elsevier Ltd</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-dadb82d7ddf96a1fdff01f9719a0059754795e1ec7badf7dcaabe9e73d5a39483</citedby><cites>FETCH-LOGICAL-c412t-dadb82d7ddf96a1fdff01f9719a0059754795e1ec7badf7dcaabe9e73d5a39483</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2005.12.053$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17667862$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16431121$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rivara, Silvia</creatorcontrib><creatorcontrib>Diamantini, Giuseppe</creatorcontrib><creatorcontrib>Di Giacomo, Barbara</creatorcontrib><creatorcontrib>Lamba, Doriano</creatorcontrib><creatorcontrib>Gatti, Giuseppe</creatorcontrib><creatorcontrib>Lucini, Valeria</creatorcontrib><creatorcontrib>Pannacci, Marilou</creatorcontrib><creatorcontrib>Mor, Marco</creatorcontrib><creatorcontrib>Spadoni, Gilberto</creatorcontrib><creatorcontrib>Tarzia, Giorgio</creatorcontrib><title>Reassessing the melatonin pharmacophore—Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>3-(Acetylaminomethyl)-2-(ethoxycarbonyl)-6-methoxy-1,3,4,5-tetrahydrobenzo[
cd]indole (
2) is a rigid melatonin analogue that as a racemate displays about the same affinity and intrinsic activity of melatonin (
1) in in vitro experiments. We report here the resolution of the racemate by preparative medium pressure liquid chromatography (MPLC) and the X-ray determination of the
R absolute configuration of the (−)-enantiomer. The two enantiomers were separately tested as MT
1 and MT
2 ligands, and the (+)-(
S)-
2 showed a potency comparable to that of melatonin and about three orders of magnitude greater than that of its enantiomer. The information obtained by crystallographic analysis and NMR studies about the conformational preference for
2 and by the pharmacological characterization of (
R)-
2 and (
S)-
2 was employed in a molecular modeling study, aimed at reassessing the melatonin receptor pharmacophore model for agonist compounds. Chiral enantioselective agonists reported in the literature were also included in the study.</description><subject>3T3 Cells</subject><subject>Animals</subject><subject>Binding, Competitive - drug effects</subject><subject>Biological and medical sciences</subject><subject>Conformational analysis</subject><subject>Crystallography, X-Ray</subject><subject>Enantiomeric resolution</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medical sciences</subject><subject>Melatonin</subject><subject>Melatonin - analogs & derivatives</subject><subject>Melatonin - chemistry</subject><subject>Melatonin - pharmacology</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Molecular modeling</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacophore model</subject><subject>Receptors, Melatonin - metabolism</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>X-ray crystal structure</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2OEzEQhVsIxISBA7BB3sAqHVz957ZYjUbDjzQSEoK1VbGrE0duO9jdI2XHITgJR-IkOEpEdrByWfreq9J7RfES-Ao4dG93q_WoVxXn7QqqFW_rR8UCmq4p61rC42LBZdeXvJfdVfEspR3nvGokPC2uoGtqgAoWxa8vhClRStZv2LQlNpLDKXjr2X6LcUQd9tsQ6fePn3ce_WTDSNFqFikFN-evX_4FXdhYjY6hnuyDnQ5LlqY462mOxNCjOySblnkybAyO9Oww5smQO-4OA0Omg88StJ4M01sbs9nlnqNF2Mz0vHgyoEv04vxeF9_e3329_Vjef_7w6fbmvtQNVFNp0Kz7yghjBtkhDGYYOAxSgMQcmBRtI2RLQFqs0QzCaMQ1SRK1abGWTV9fF29OvvsYvs-UJjXapMk59BTmpDrRV7IH8V8QBIhOiDaDcAJ1DClFGtQ-2hHjQQFXx0bVTuVG1bFRBZXKjWbNq7P5vB7JXBTnCjPw-gxgyukPEb226cKJLh_aVZl7d-IoZ_ZgKaqkLXlNxkbSkzLB_uOMP6S1xfw</recordid><startdate>20060515</startdate><enddate>20060515</enddate><creator>Rivara, Silvia</creator><creator>Diamantini, Giuseppe</creator><creator>Di Giacomo, Barbara</creator><creator>Lamba, Doriano</creator><creator>Gatti, Giuseppe</creator><creator>Lucini, Valeria</creator><creator>Pannacci, Marilou</creator><creator>Mor, Marco</creator><creator>Spadoni, Gilberto</creator><creator>Tarzia, Giorgio</creator><general>Elsevier Ltd</general><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060515</creationdate><title>Reassessing the melatonin pharmacophore—Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue</title><author>Rivara, Silvia ; Diamantini, Giuseppe ; Di Giacomo, Barbara ; Lamba, Doriano ; Gatti, Giuseppe ; Lucini, Valeria ; Pannacci, Marilou ; Mor, Marco ; Spadoni, Gilberto ; Tarzia, Giorgio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-dadb82d7ddf96a1fdff01f9719a0059754795e1ec7badf7dcaabe9e73d5a39483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>3T3 Cells</topic><topic>Animals</topic><topic>Binding, Competitive - drug effects</topic><topic>Biological and medical sciences</topic><topic>Conformational analysis</topic><topic>Crystallography, X-Ray</topic><topic>Enantiomeric resolution</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Medical sciences</topic><topic>Melatonin</topic><topic>Melatonin - analogs & derivatives</topic><topic>Melatonin - chemistry</topic><topic>Melatonin - pharmacology</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Molecular modeling</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacophore model</topic><topic>Receptors, Melatonin - metabolism</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>X-ray crystal structure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rivara, Silvia</creatorcontrib><creatorcontrib>Diamantini, Giuseppe</creatorcontrib><creatorcontrib>Di Giacomo, Barbara</creatorcontrib><creatorcontrib>Lamba, Doriano</creatorcontrib><creatorcontrib>Gatti, Giuseppe</creatorcontrib><creatorcontrib>Lucini, Valeria</creatorcontrib><creatorcontrib>Pannacci, Marilou</creatorcontrib><creatorcontrib>Mor, Marco</creatorcontrib><creatorcontrib>Spadoni, Gilberto</creatorcontrib><creatorcontrib>Tarzia, Giorgio</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rivara, Silvia</au><au>Diamantini, Giuseppe</au><au>Di Giacomo, Barbara</au><au>Lamba, Doriano</au><au>Gatti, Giuseppe</au><au>Lucini, Valeria</au><au>Pannacci, Marilou</au><au>Mor, Marco</au><au>Spadoni, Gilberto</au><au>Tarzia, Giorgio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Reassessing the melatonin pharmacophore—Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2006-05-15</date><risdate>2006</risdate><volume>14</volume><issue>10</issue><spage>3383</spage><epage>3391</epage><pages>3383-3391</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>3-(Acetylaminomethyl)-2-(ethoxycarbonyl)-6-methoxy-1,3,4,5-tetrahydrobenzo[
cd]indole (
2) is a rigid melatonin analogue that as a racemate displays about the same affinity and intrinsic activity of melatonin (
1) in in vitro experiments. We report here the resolution of the racemate by preparative medium pressure liquid chromatography (MPLC) and the X-ray determination of the
R absolute configuration of the (−)-enantiomer. The two enantiomers were separately tested as MT
1 and MT
2 ligands, and the (+)-(
S)-
2 showed a potency comparable to that of melatonin and about three orders of magnitude greater than that of its enantiomer. The information obtained by crystallographic analysis and NMR studies about the conformational preference for
2 and by the pharmacological characterization of (
R)-
2 and (
S)-
2 was employed in a molecular modeling study, aimed at reassessing the melatonin receptor pharmacophore model for agonist compounds. Chiral enantioselective agonists reported in the literature were also included in the study.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>16431121</pmid><doi>10.1016/j.bmc.2005.12.053</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2006-05, Vol.14 (10), p.3383-3391 |
| issn | 0968-0896 1464-3391 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67829817 |
| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | 3T3 Cells Animals Binding, Competitive - drug effects Biological and medical sciences Conformational analysis Crystallography, X-Ray Enantiomeric resolution Magnetic Resonance Spectroscopy Medical sciences Melatonin Melatonin - analogs & derivatives Melatonin - chemistry Melatonin - pharmacology Mice Models, Molecular Molecular modeling Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Pharmacophore model Receptors, Melatonin - metabolism Stereoisomerism Structure-Activity Relationship X-ray crystal structure |
| title | Reassessing the melatonin pharmacophore—Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T19%3A11%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Reassessing%20the%20melatonin%20pharmacophore%E2%80%94Enantiomeric%20resolution,%20pharmacological%20activity,%20structure%20analysis,%20and%20molecular%20modeling%20of%20a%20constrained%20chiral%20melatonin%20analogue&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry&rft.au=Rivara,%20Silvia&rft.date=2006-05-15&rft.volume=14&rft.issue=10&rft.spage=3383&rft.epage=3391&rft.pages=3383-3391&rft.issn=0968-0896&rft.eissn=1464-3391&rft_id=info:doi/10.1016/j.bmc.2005.12.053&rft_dat=%3Cproquest_cross%3E67829817%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=17176775&rft_id=info:pmid/16431121&rft_els_id=S0968089606000058&rfr_iscdi=true |