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

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 σ 1 and σ 2 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 σ 1 receptor affinity.