Novel highly potent and selective sigma 1 receptor antagonists related to spipethiane

J Med Chem. 2010 Feb 11;53(3):1261-9. doi: 10.1021/jm901542q.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Binding, Competitive
  • Breast Neoplasms / drug therapy
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Proliferation / drug effects
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Drug Screening Assays, Antitumor
  • Female
  • Guinea Pigs
  • Humans
  • Ileum / cytology
  • Ileum / drug effects
  • Jurkat Cells / drug effects
  • Male
  • Mice
  • Molecular Structure
  • Pain Measurement
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacology*
  • Radioligand Assay
  • Rats
  • Receptors, sigma / antagonists & inhibitors*
  • Sigma-1 Receptor
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry*
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Antineoplastic Agents
  • Piperidines
  • Receptors, sigma
  • Spiro Compounds
  • spipethiane