High-Affinity, Selective s Ligands of the 1,2,3,4-Tetrahydro-1,4′-silaspiro[naphthalene-1,4′-piperidine] Type: Syntheses, Structures, and Pharmacological Properties

The 1'-organyl-1,2,3,4-tetrahydrospiro[naphthalene-1,4'-piperidine] derivatives 1?a-4?a [for which organyl=benzyl (1a), 4-methoxybenzyl (2?a), 2-phenylethyl (3?a), or 3-methylbut-2-enyl (4?a)] are high-affinity, selective s1 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 center dot HCl4?b center dot HCl. Compounds 1?a center dot HCl4?a center dot HCl and 1?b center dot HCl4?b center dot HCl were structurally characterized by NMR spectroscopy (1H, 13C, 29Si) in solution, and the C/Si analogues 3?a center dot HCl and 3?b center dot HCl were studied by single-crystal X-ray diffraction. These structural investigations were complemented by computational studies. The s1 and s2 receptor affinities of the C/Si pairs 1?a/1?b-4?a/4?b were studied with radioligand binding assays. The s1 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 s2 receptor is decreased by the C/Si exchange, the sigma 1/sigma 2 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.