Synthesis and Pharmacological Characterization of Sila-panamesine, a Sila-Analogue of the σ Receptor Ligand Panamesine (EMD 57445)

Abstract

Sila-substitution (C/Si exchange) at the 4-position of the piperidine skeleton of the σ receptor ligand panamesine (1a, EMD 57445) leads to sila-panamesine (1b). Compounds 1a and 1b were synthesized in multistep syntheses, starting from 1-benzyl-4-piperidone and tetramethoxysilane, respectively, and were isolated as the hydrochlorides 1a·HCl and 1b·HCl. ESI-MS studies of aqueous solutions of the silanol 1b and the corresponding disiloxane 14 at different pH values revealed a remarkable stability of 1b. The identities of 1a·HCl and 1b·HCl were established by elemental analyses and multinuclear NMR studies. The σ1 and σ2 receptor affinities of the C/Si analogues panamesine (1a) and sila-panamesine (1b) were determined in competitive radioligand receptor binding studies. It was shown that the C/Si exchange results in a 3-fold enhancement of σ1 receptor affinity.