Sila-Analogues of High-Affinity, Selective σ Ligands of the Spiro[indane-1,4‘-piperidine] Type:  Syntheses, Structures, and Pharmacological Properties

The 1‘-organylspiro[indane-1,4‘-piperidine] derivatives 1a − 4a (organyl = benzyl ( 1a ), 4-methoxybenzyl ( 2a ), 2-phenylethyl ( 3a ), 3-methylbut-2-enyl ( 4a )) are high-affinity, selective σ ligands. The corresponding sila-analogues 1b − 4b (→ replacement of the carbon spirocenter by a silicon atom) were synthesized in three-step syntheses, starting from dichlorodivinylsilane, and were isolated as the hydrochlorides 1b ·HCl− 4b ·HCl. To get information about the structure of the title compounds and their respective carbon analogues in the solid state and in solution, crystal structure analyses ( 1a ·HCl, 2a, 2b ·HCl) and temperature-dependent solution 1 H NMR studies ( 2a ·HCl, 2b ·HCl) were performed. These structural investigations were complemented by computational studies of related model species. The C/Si pairs 1a / 1b − 4a / 4b were studied for their affinities for various central nervous system receptors (σ, 5-HT 1A, 5-HT 2A, α 1, α 2, M, D 2 ) using radioligand binding assays. The σ affinities of the sila-analogues 2b − 4b were found to be similar to those of the parent carbon compounds 2a − 4a, whereas sila-substitution of 1a (→ 1b ) resulted in a decrease of affinity of about 1 order of magnitude. On the other hand, a significant increase of affinity for the dopamine D 2 and the serotonin 2A (5-HT 2A ) receptors was observed for the sila-analogues 1b − 4b, the sila-substitution effect being especially pronounced for 4a / 4b (6-fold affinity increase for the D 2 receptor) and 3a / 3b (37-fold affinity increase for the 5-HT 2A receptor).