New Series of Morpholine and 1,4-Oxazepane Derivatives as Dopamine D4 Receptor Ligands: Synthesis and 3D-QSAR Model
Since the identification of the dopamine D4 receptor subtype and speculations about its possible involvement in schizophrenia, much work has been put into development of selective D4 ligands. These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work descr...
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| Veröffentlicht in: | Journal of medicinal chemistry 2004-06, Vol.47 (12), p.3089-3104 |
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| container_end_page | 3104 |
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| container_issue | 12 |
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| container_title | Journal of medicinal chemistry |
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| creator | Audouze, Karine Nielsen, Elsebet Østergaard Peters, Dan |
| description | Since the identification of the dopamine D4 receptor subtype and speculations about its possible involvement in schizophrenia, much work has been put into development of selective D4 ligands. These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work describes the synthesis of a new series of 2,4-disubstituted morpholines and 2,4-disubstituted 1,4-oxazepanes with selectivity for the dopamine D4 receptor. A 3D-QSAR analysis using the GRID/GOLPE methodology was performed with the purpose to get a better understanding of the relationship between chemical structure and biological activity. Inspection of the coefficient plots allowed us to identify that regions which are important for affinity are situated around the two benzene ring systems, a p-chlorobenzyl group, and the aliphatic amine belonging to the morpholine or 1,4-oxazepane system. In addition, the size of the morpholine or 1,4-oxazepane ring seems to be important for affinity. |
| doi_str_mv | 10.1021/jm031111m |
| format | Article |
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These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work describes the synthesis of a new series of 2,4-disubstituted morpholines and 2,4-disubstituted 1,4-oxazepanes with selectivity for the dopamine D4 receptor. A 3D-QSAR analysis using the GRID/GOLPE methodology was performed with the purpose to get a better understanding of the relationship between chemical structure and biological activity. Inspection of the coefficient plots allowed us to identify that regions which are important for affinity are situated around the two benzene ring systems, a p-chlorobenzyl group, and the aliphatic amine belonging to the morpholine or 1,4-oxazepane system. In addition, the size of the morpholine or 1,4-oxazepane ring seems to be important for affinity.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm031111m</identifier><identifier>PMID: 15163190</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Catecholaminergic system ; CHO Cells ; Cricetinae ; Humans ; Medical sciences ; Models, Molecular ; Molecular Conformation ; Morpholines - chemical synthesis ; Morpholines - chemistry ; Morpholines - pharmacology ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Oxazepam - analogs & derivatives ; Oxazepam - chemical synthesis ; Oxazepam - chemistry ; Oxazepam - pharmacology ; Pharmacology. Drug treatments ; Quantitative Structure-Activity Relationship ; Radioligand Assay ; Receptors, Dopamine D2 - chemistry ; Receptors, Dopamine D2 - drug effects ; Receptors, Dopamine D2 - metabolism ; Receptors, Dopamine D4</subject><ispartof>Journal of medicinal chemistry, 2004-06, Vol.47 (12), p.3089-3104</ispartof><rights>Copyright © 2004 American Chemical Society</rights><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm031111m$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm031111m$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15793248$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15163190$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Audouze, Karine</creatorcontrib><creatorcontrib>Nielsen, Elsebet Østergaard</creatorcontrib><creatorcontrib>Peters, Dan</creatorcontrib><title>New Series of Morpholine and 1,4-Oxazepane Derivatives as Dopamine D4 Receptor Ligands: Synthesis and 3D-QSAR Model</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Since the identification of the dopamine D4 receptor subtype and speculations about its possible involvement in schizophrenia, much work has been put into development of selective D4 ligands. These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work describes the synthesis of a new series of 2,4-disubstituted morpholines and 2,4-disubstituted 1,4-oxazepanes with selectivity for the dopamine D4 receptor. A 3D-QSAR analysis using the GRID/GOLPE methodology was performed with the purpose to get a better understanding of the relationship between chemical structure and biological activity. Inspection of the coefficient plots allowed us to identify that regions which are important for affinity are situated around the two benzene ring systems, a p-chlorobenzyl group, and the aliphatic amine belonging to the morpholine or 1,4-oxazepane system. In addition, the size of the morpholine or 1,4-oxazepane ring seems to be important for affinity.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Catecholaminergic system</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Morpholines - chemical synthesis</subject><subject>Morpholines - chemistry</subject><subject>Morpholines - pharmacology</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Oxazepam - analogs & derivatives</subject><subject>Oxazepam - chemical synthesis</subject><subject>Oxazepam - chemistry</subject><subject>Oxazepam - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>Radioligand Assay</subject><subject>Receptors, Dopamine D2 - chemistry</subject><subject>Receptors, Dopamine D2 - drug effects</subject><subject>Receptors, Dopamine D2 - metabolism</subject><subject>Receptors, Dopamine D4</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpN0c1OGzEQB3CrKmpS6IEXQL70xoLHXq93e4tY2iCF8JG0Rb1Yw-6k2ZD90DqkwIkrr8mTYEia1gdbsn_-j-xhbBfEAQgJh7NSKPCjfMe6oKUIwliE71lXCCkDGUnVYR-dmwnhmVQfWAc0RAoS0WXLIf3hI2oLcrye8NO6bab1vKiIY5Vz2A-Dszt8oAb9TurZEhfF0lt0PK0bLF9lGvJLyqhZ1C0fFL_9Rffl-fGJj-6rxZRc4d6yVBpcjHqXvkRO8x22NcG5o0_rdZt9_3o8PuoHg7NvJ0e9QYAgQQQZgsAEQ1KGjI4QdAwqj0VkDCRxHkeaYooVURZqIkyMQGX8rKNMR5SD2mZ7q9zm9rqk3DZtUWJ7b_9-gAef1wBdhvNJi1VWuP-cSZQMY--ClSvcgu4259je2Mgoo-34fGR_9OXP_tXwl03_5WLm7Ky-bSv_TAvCvjbMbhqmXgC9EIL3</recordid><startdate>20040603</startdate><enddate>20040603</enddate><creator>Audouze, Karine</creator><creator>Nielsen, Elsebet Østergaard</creator><creator>Peters, Dan</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></search><sort><creationdate>20040603</creationdate><title>New Series of Morpholine and 1,4-Oxazepane Derivatives as Dopamine D4 Receptor Ligands: Synthesis and 3D-QSAR Model</title><author>Audouze, Karine ; Nielsen, Elsebet Østergaard ; Peters, Dan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a1210-ca10a9a4e37e756a15813d80677198d865e8e83eec45eea970a3797056c56ed13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Catecholaminergic system</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Morpholines - chemical synthesis</topic><topic>Morpholines - chemistry</topic><topic>Morpholines - pharmacology</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Oxazepam - analogs & derivatives</topic><topic>Oxazepam - chemical synthesis</topic><topic>Oxazepam - chemistry</topic><topic>Oxazepam - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Quantitative Structure-Activity Relationship</topic><topic>Radioligand Assay</topic><topic>Receptors, Dopamine D2 - chemistry</topic><topic>Receptors, Dopamine D2 - drug effects</topic><topic>Receptors, Dopamine D2 - metabolism</topic><topic>Receptors, Dopamine D4</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Audouze, Karine</creatorcontrib><creatorcontrib>Nielsen, Elsebet Østergaard</creatorcontrib><creatorcontrib>Peters, Dan</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Audouze, Karine</au><au>Nielsen, Elsebet Østergaard</au><au>Peters, Dan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New Series of Morpholine and 1,4-Oxazepane Derivatives as Dopamine D4 Receptor Ligands: Synthesis and 3D-QSAR Model</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2004-06-03</date><risdate>2004</risdate><volume>47</volume><issue>12</issue><spage>3089</spage><epage>3104</epage><pages>3089-3104</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Since the identification of the dopamine D4 receptor subtype and speculations about its possible involvement in schizophrenia, much work has been put into development of selective D4 ligands. These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work describes the synthesis of a new series of 2,4-disubstituted morpholines and 2,4-disubstituted 1,4-oxazepanes with selectivity for the dopamine D4 receptor. A 3D-QSAR analysis using the GRID/GOLPE methodology was performed with the purpose to get a better understanding of the relationship between chemical structure and biological activity. Inspection of the coefficient plots allowed us to identify that regions which are important for affinity are situated around the two benzene ring systems, a p-chlorobenzyl group, and the aliphatic amine belonging to the morpholine or 1,4-oxazepane system. In addition, the size of the morpholine or 1,4-oxazepane ring seems to be important for affinity.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>15163190</pmid><doi>10.1021/jm031111m</doi><tpages>16</tpages></addata></record> |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Biological and medical sciences Catecholaminergic system CHO Cells Cricetinae Humans Medical sciences Models, Molecular Molecular Conformation Morpholines - chemical synthesis Morpholines - chemistry Morpholines - pharmacology Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Oxazepam - analogs & derivatives Oxazepam - chemical synthesis Oxazepam - chemistry Oxazepam - pharmacology Pharmacology. Drug treatments Quantitative Structure-Activity Relationship Radioligand Assay Receptors, Dopamine D2 - chemistry Receptors, Dopamine D2 - drug effects Receptors, Dopamine D2 - metabolism Receptors, Dopamine D4 |
| title | New Series of Morpholine and 1,4-Oxazepane Derivatives as Dopamine D4 Receptor Ligands: Synthesis and 3D-QSAR Model |
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