| Thiophene bioisosteres of spirocyclic sigma receptor ligands: Relationships between substitution pattern and receptor affinity. | |
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MedLine Citation:
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PMID: 22515405 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Based on the 6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] framework a series of more than 30 ligands with versatile substituents in 1-, 2'- and 6'-position has been synthesized and pharmacologically evaluated in order to find novel structure-affinity relationships. It was found that a cyclohexylmethyl residue at the piperidine N-atom instead of a benzyl moiety led to increased σ2 affinity and therefore to decreased σ1/σ2 selectivity. Small substituents (e.g. OH, OCH3, CN, CH2OH) in 6'-position adjacent to the O-atom were well tolerated by the σ1 receptor. Removal of the substituent in 6'-position resulted in very potent but unselective σ ligands (13). A broad range of substituents with various lipophilic and H-bond forming properties was introduced in 2'-position adjacent to the S-atom without loss of σ1 affinity. However, very polar and basic substituents in both 2'- and 6'-position decreased the σ1 affinity considerably. It is postulated that the electron density of the thiophene moiety has a big impact on the σ1 affinity. |
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Authors:
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Christoph Oberdorf; Dirk Schepmann; Jose Miguel Vela; Helmut Buschmann; Joerg Holenz; Bernhard Wünsch |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-4-19 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: - ISSN: 1520-4804 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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