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.