title: 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.
authors.affiliation: Dipartimento Farmacochimico, Università di Bari, via Orabona 4, I-70125 Bari, Italy. berardi@farmchim.uniba.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Savina
authors.initials: S
authors.lastname: Ferorelli
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.forename: Maria P
authors.initials: MP
authors.lastname: Pedone
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D008745:Methylation; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists / Q000737:chemistry*; D013251:Steroid Isomerases / Q000737:chemistry; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D009281:Naphthalenes; D010880:Piperidines; D017480:Receptors, sigma; D013251:Steroid Isomerases; C022669:delta(8)-delta(7)-sterol isomerase