Sila-haloperidol: A Silicon Analogue of the Dopamine (D 2 ) Receptor Antagonist Haloperidol

Haloperidol ( 1a ), a dopamine (D 2 ) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1a (R 3 C OH → R 3 Si OH) leads to sila-haloperidol ( 1b ). Sila-haloperidol was synthesized in a multistep synthesis, starting from tetramethoxysilane, and was isolated as the hydrochloride 1b ·HCl. ESI-MS studies of aqueous solutions of the silanol 1b and the corresponding disiloxane 10 at different pH values revealed a remarkable stability of 1b . The C/Si analogues 1a ·HCl and 1b ·HCl were structurally characterized by single-crystal X-ray diffraction and solution ([D 6 ]DMSO) NMR spectroscopy. Analogous chair conformations of the piperidinium ( 1a ·HCl) and 4-silapiperidinium ( 1b ·HCl) skeleton were observed in the crystal, and two analogous chair conformations of the cations were detected in solution, the molar ratios of these two conformers differing substantially ( 1a ·HCl, 13:1; 1b ·HCl, 2:1). In radioligand binding studies, the C/Si analogues 1a and 1b displayed similar potencies at recombinant human dopamine hD 1, hD 4, and hD 5 receptors, whereas the silicon compound 1b was 4.7-fold more potent at hD 2 receptors than its carbon analogue 1a; i.e., sila-substitution of haloperidol has changed the receptor selectivity profile.