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

Abstract

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 1H 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-HT1A, 5-HT2A, α1, α2, M, D2) 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 D2 and the serotonin 2A (5-HT2A) 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 D2 receptor) and 3a/3b (37-fold affinity increase for the 5-HT2A receptor).