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.