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 sigma1 receptor

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 -subtype affinities and selectivities by radioligand binding assays at and 2 receptors and Δ8- Δ7 sterol isomerase (SI) site. 4-Methyl derivative 31 was the most potent 1 ligand (Ki = 0.030 nM) with a good selectivity profile (597-fold and 268-fold relative to 2 receptor and SI site, respectively), whereas 3,3-dimethyl derivative 26 (Ki = 0.035 nM) was the most selective (680-fold) relative to the 2 receptor. Both compounds can be proposed as tools for PET experiments. Furthemore, the naphthalene compounds 26, 28, 31, and 33 demonstrated antiproliferative activity in rat C6 glioma cells (EC50 = 15.0μM for 33), revealing a putative 1 antagonist activity and opening a useful perspective in tumor research and therapy.