title: High-affinity, selective σ ligands of the 1,2,3,4-tetrahydro-1,4'-silaspiro[naphthalene-1,4'-piperidine] type: syntheses, structures, and pharmacological properties.
abstract: The 1'-organyl-1,2,3,4-tetrahydrospiro[naphthalene-1,4'-piperidine] derivatives 1 a-4 a [for which organyl=benzyl (1 a), 4-methoxybenzyl (2 a), 2-phenylethyl (3 a), or 3-methylbut-2-enyl (4 a)] are high-affinity, selective σ₁ ligands. The corresponding sila-analogues 1 b-4 b (replacement of the carbon spirocenter with a silicon atom) were synthesized in multistep syntheses, starting from dichlorodivinylsilane, and were isolated as the hydrochlorides 1 b⋅HCl-4 b⋅HCl. Compounds 1 a⋅HCl-4 a⋅HCl and 1 b⋅HCl-4 b⋅HCl were structurally characterized by NMR spectroscopy (¹H, ¹³C, ²⁹Si) in solution, and the C/Si analogues 3 a⋅HCl and 3 b⋅HCl were studied by single-crystal X-ray diffraction. These structural investigations were complemented by computational studies. The σ₁ and σ₂ receptor affinities of the C/Si pairs 1 a/1 b-4 a/4 b were studied with radioligand binding assays. The σ₁ receptor affinity of the silicon compounds 1 b-4 b is slightly higher than that of the corresponding carbon analogues 1 a-4 a. Because affinity for the σ₂ receptor is decreased by the C/Si exchange, the σ₁/σ₂ selectivity of the silicon compounds is considerably improved, indicating that the C→Si switch strategy is a powerful tool for modulating both pharmacological potency and selectivity.
authors.affiliation: Institut für Anorganische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany. r.tacke@uni-wuerzburg.de
authors.forename: Reinhold
authors.initials: R
authors.lastname: Tacke
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Bertermann
authors.forename: Christian
authors.initials: C
authors.lastname: Burschka
authors.forename: Steffen
authors.initials: S
authors.lastname: Dörrich
authors.forename: Markus
authors.initials: M
authors.lastname: Fischer
authors.forename: Barbara
authors.initials: B
authors.lastname: Müller
authors.forename: Géraldine
authors.initials: G
authors.lastname: Meyerhans
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.forename: Ingvar
authors.initials: I
authors.lastname: Arnason
authors.forename: Ragnar
authors.initials: R
authors.lastname: Bjornsson
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002244:Carbon / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D012825:Silicon / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D009281:Naphthalenes; D018696:Neuroprotective Agents; D010880:Piperidines; D017480:Receptors, sigma; D002244:Carbon; D012825:Silicon