Piperidinyltetralin .sigma. Ligands
Sigma receptor ligands have been proposed to be potential antipsychotic drugs based on their activity profile in animal behavioral models and their indirect modulation of dopaminergic function. Compound 15 (DuP 734) is a combined antagonist of sigma-1 and serotonin 5HT2 receptors, which has been ent...
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| Veröffentlicht in: | Journal of medicinal chemistry 1994-02, Vol.37 (3), p.364-370 |
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| container_end_page | 370 |
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| container_issue | 3 |
| container_start_page | 364 |
| container_title | Journal of medicinal chemistry |
| container_volume | 37 |
| creator | Gilligan, Paul J Kergaye, Ahmed A Lewis, Bryan M McElroy, John F |
| description | Sigma receptor ligands have been proposed to be potential antipsychotic drugs based on their activity profile in animal behavioral models and their indirect modulation of dopaminergic function. Compound 15 (DuP 734) is a combined antagonist of sigma-1 and serotonin 5HT2 receptors, which has been entered into phase I clinical trials as a potential antipsychotic drug. Tetralins 1 and 2 were prepared to determine whether restriction of the conformation of 15 and its analogs may lead to differences in binding selectivity or in vivo profile. The syntheses and the structure-activity relationships of these compounds are reported herein. A reduced derivative, 14, had high affinity for sigma-1 and serotonin 5HT2 receptors as well as excellent oral activity in some animal antipsychotic models. Furthermore, compound 14 failed to cause catalepsy in the rat up to 90 mg/kg (po). |
| doi_str_mv | 10.1021/jm00029a008 |
| format | Article |
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A reduced derivative, 14, had high affinity for sigma-1 and serotonin 5HT2 receptors as well as excellent oral activity in some animal antipsychotic models. 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Ligands</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Sigma receptor ligands have been proposed to be potential antipsychotic drugs based on their activity profile in animal behavioral models and their indirect modulation of dopaminergic function. Compound 15 (DuP 734) is a combined antagonist of sigma-1 and serotonin 5HT2 receptors, which has been entered into phase I clinical trials as a potential antipsychotic drug. Tetralins 1 and 2 were prepared to determine whether restriction of the conformation of 15 and its analogs may lead to differences in binding selectivity or in vivo profile. The syntheses and the structure-activity relationships of these compounds are reported herein. A reduced derivative, 14, had high affinity for sigma-1 and serotonin 5HT2 receptors as well as excellent oral activity in some animal antipsychotic models. Furthermore, compound 14 failed to cause catalepsy in the rat up to 90 mg/kg (po).</description><subject>Aggression - drug effects</subject><subject>Animals</subject><subject>Antipsychotic Agents - chemical synthesis</subject><subject>Antipsychotic Agents - metabolism</subject><subject>Antipsychotic Agents - pharmacology</subject><subject>Behavior, Animal - drug effects</subject><subject>Chemistry</subject><subject>Exact sciences and technology</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with only one n hetero atom and condensed derivatives</subject><subject>Ligands</subject><subject>Mescaline - antagonists & inhibitors</subject><subject>Mescaline - pharmacology</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Organic chemistry</subject><subject>Piperidines - chemical synthesis</subject><subject>Piperidines - metabolism</subject><subject>Piperidines - pharmacology</subject><subject>Preparations and properties</subject><subject>Receptors, Serotonin - metabolism</subject><subject>Receptors, sigma - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Tetrahydronaphthalenes - pharmacology</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>eNpt0MtLw0AQBvBFFK2Pk2dBUPQgqbOzSXZzFPGFxQetxdsy2WzK1iStuynof2-kpXjwNDDfj2H4GDvk0OeA_HJaAwBmBKA2WI8nCFGsIN5kvW6NEaYodthuCNOOCY5im23LDJIM0x47eXFz613hmu-qta2nyjXH_eAmNfWPB25CTRH22VZJVbAHq7nH3m5vRtf30eD57uH6ahCRUKKNVEloYhAyNlmcKBScyixFkgWQshxLY_KS5wnlQAVXMi-xsEaQkBwRCiX22Nny7tzPPhc2tLp2wdiqosbOFkHLVCQgETp4sYTGz0LwttRz72ry35qD_q1E_6mk00ers4u8tsXarjro8tNVTsFQVXpqjAtrJrJYIecdi5bMhdZ-rWPyHzqVQiZ69DLUQ3U7fn98etXjzp8vPZmgp7OFb7ru_n3wB3MBgqs</recordid><startdate>19940201</startdate><enddate>19940201</enddate><creator>Gilligan, Paul J</creator><creator>Kergaye, Ahmed A</creator><creator>Lewis, Bryan M</creator><creator>McElroy, John F</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>19940201</creationdate><title>Piperidinyltetralin .sigma. Ligands</title><author>Gilligan, Paul J ; Kergaye, Ahmed A ; Lewis, Bryan M ; McElroy, John F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a383t-8fa2c40374c9458231af962a7d0a8e12fccbf1b5ab0ad187bf2dec3a371220d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Aggression - drug effects</topic><topic>Animals</topic><topic>Antipsychotic Agents - chemical synthesis</topic><topic>Antipsychotic Agents - metabolism</topic><topic>Antipsychotic Agents - pharmacology</topic><topic>Behavior, Animal - drug effects</topic><topic>Chemistry</topic><topic>Exact sciences and technology</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with only one n hetero atom and condensed derivatives</topic><topic>Ligands</topic><topic>Mescaline - antagonists & inhibitors</topic><topic>Mescaline - pharmacology</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Organic chemistry</topic><topic>Piperidines - chemical synthesis</topic><topic>Piperidines - metabolism</topic><topic>Piperidines - pharmacology</topic><topic>Preparations and properties</topic><topic>Receptors, Serotonin - metabolism</topic><topic>Receptors, sigma - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Tetrahydronaphthalenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gilligan, Paul J</creatorcontrib><creatorcontrib>Kergaye, Ahmed A</creatorcontrib><creatorcontrib>Lewis, Bryan M</creatorcontrib><creatorcontrib>McElroy, John F</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>Gilligan, Paul J</au><au>Kergaye, Ahmed A</au><au>Lewis, Bryan M</au><au>McElroy, John F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Piperidinyltetralin .sigma. Ligands</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1994-02-01</date><risdate>1994</risdate><volume>37</volume><issue>3</issue><spage>364</spage><epage>370</epage><pages>364-370</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Sigma receptor ligands have been proposed to be potential antipsychotic drugs based on their activity profile in animal behavioral models and their indirect modulation of dopaminergic function. Compound 15 (DuP 734) is a combined antagonist of sigma-1 and serotonin 5HT2 receptors, which has been entered into phase I clinical trials as a potential antipsychotic drug. Tetralins 1 and 2 were prepared to determine whether restriction of the conformation of 15 and its analogs may lead to differences in binding selectivity or in vivo profile. The syntheses and the structure-activity relationships of these compounds are reported herein. A reduced derivative, 14, had high affinity for sigma-1 and serotonin 5HT2 receptors as well as excellent oral activity in some animal antipsychotic models. Furthermore, compound 14 failed to cause catalepsy in the rat up to 90 mg/kg (po).</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>7905926</pmid><doi>10.1021/jm00029a008</doi><tpages>7</tpages></addata></record> |
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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1994-02, Vol.37 (3), p.364-370 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Aggression - drug effects Animals Antipsychotic Agents - chemical synthesis Antipsychotic Agents - metabolism Antipsychotic Agents - pharmacology Behavior, Animal - drug effects Chemistry Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with only one n hetero atom and condensed derivatives Ligands Mescaline - antagonists & inhibitors Mescaline - pharmacology Mice Molecular Structure Organic chemistry Piperidines - chemical synthesis Piperidines - metabolism Piperidines - pharmacology Preparations and properties Receptors, Serotonin - metabolism Receptors, sigma - metabolism Structure-Activity Relationship Tetrahydronaphthalenes - pharmacology |
| title | Piperidinyltetralin .sigma. Ligands |
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