Abstract
Conservative chemical modifications of the core structure of the lead spipethiane (1) afforded novel potent sigma(1) ligands. sigma(1) affinity and sigma(1/)sigma(2) selectivity proved to be favored by the introduction of polar functions (oxygen atom or carbonyl group) in position 3 or 4 (4-6) or by the elongation of the distance between the two hydrophobic portions of the molecule with the simultaneous presence of a carbonyl group in position 4 (8 and 9). The observed cytostatic effect against the human breast cancer cell line MCF-7/ADR, highly expressing sigma(1) receptors, and not against MCF-7, as well as the enhancement of morphine analgesia highlighted the sigma(1) antagonist profile of this series of compounds. In particular, due to its high sigma(1) affinity (pK(i) = 10.28) and sigma(1)/sigma(2) selectivity ratio (29510), compound 9 might be a novel valuable tool for sigma receptor characterization and a suitable template for the rational design of potential therapeutically useful sigma(1) antagonists.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics / chemical synthesis
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Analgesics / chemistry
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Analgesics / pharmacology*
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Binding, Competitive
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Breast Neoplasms / drug therapy
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Membrane / drug effects
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Cell Proliferation / drug effects
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Cerebral Cortex / cytology
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Cerebral Cortex / drug effects
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Drug Screening Assays, Antitumor
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Female
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Guinea Pigs
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Humans
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Ileum / cytology
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Ileum / drug effects
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Jurkat Cells / drug effects
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Male
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Mice
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Molecular Structure
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Pain Measurement
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / pharmacology*
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Radioligand Assay
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Rats
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Receptors, sigma / antagonists & inhibitors*
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Sigma-1 Receptor
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry*
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
Substances
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Analgesics
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Antineoplastic Agents
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Piperidines
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Receptors, sigma
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Spiro Compounds
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spipethiane