Sila-haloperidol: A Silicon Analogue of the Dopamine (D2) Receptor Antagonist Haloperidol

Abstract

Haloperidol (1a), a dopamine (D2) 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 (R3COH → R3SiOH) 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 ([D6]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 hD1, hD4, and hD5 receptors, whereas the silicon compound 1b was 4.7-fold more potent at hD2 receptors than its carbon analogue 1a; i.e., sila-substitution of haloperidol has changed the receptor selectivity profile.