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Methyl substitution on the piperidine ring of N-[omega-(6-methoxynaphthalen-1-yl)alkyl] derivatives as a probe for selective binding and activity at the sigma(1) receptor.

Abstract
The N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl and N-(6-methoxynaphthalen-1-yl)propyl derivatives as well as their upper homologous butyl derivatives of various methylpiperidines were prepared. The piperidine moiety bearing monomethyl or geminal dimethyl groups was employed as a probe to explore sigma-subtype affinities and selectivities by radioligand binding assays at sigma(1) and sigma(2) receptors and the Delta(8)-Delta(7) sterol isomerase (SI) site. 4-Methyl derivative 31 was the most potent sigma(1) ligand (K(i)=0.030 nM) with a good selectivity profile (597-fold and 268-fold relative to sigma(2) receptor and SI site, respectively), whereas 3,3-dimethyl derivative 26 (K(i)=0.35 nM) was the most selective (680-fold) relative to the sigma(2) receptor. Both compounds can be proposed as tools for PET experiments. Furthermore, the naphthalene compounds 26, 28, 31, and 33 demonstrated antiproliferative activity in rat C6 glioma cells (EC(50) = 15.0 microM for 33), revealing a putative sigma(1) antagonist activity and opening a useful perspective in tumor research and therapy.
AuthorsFrancesco Berardi, Savina Ferorelli, Carmen Abate, Maria P Pedone, Nicola A Colabufo, Marialessandra Contino, Roberto Perrone
JournalJournal of medicinal chemistry (J Med Chem) Vol. 48 Issue 26 Pg. 8237-44 (Dec 29 2005) ISSN: 0022-2623 [Print] United States
PMID16366605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Naphthalenes
  • Piperidines
  • Receptors, sigma
  • Steroid Isomerases
  • delta(8)-delta(7)-sterol isomerase
Topics
  • Animals
  • Cell Proliferation (drug effects)
  • Methylation
  • Naphthalenes (chemical synthesis, chemistry, pharmacology)
  • Piperidines (chemical synthesis, chemistry, pharmacology)
  • Radioligand Assay (methods)
  • Rats
  • Receptors, sigma (agonists, chemistry)
  • Steroid Isomerases (chemistry)
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

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