OBJECTIVES: The pharmacology and metabolism of the potent sigma1 receptor ligand 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] were evaluated. METHODS: The compound was tested against a wide range of receptors, ion channels and neurotransmitter transporters in radioligand binding assays. Analgesic activity was evaluated using the capsaicin pain model. Metabolism by rat and human liver microsomes was investigated, and the metabolites were identified by a variety of analytical techniques. KEY FINDINGS: 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] (compound 1) is a potent sigma1 receptor ligand (Ki 1.14 nM) with extraordinarily high sigma1/sigma2 selectivity (>1100). It was selective for the sigma1 receptor over more than 60 other receptors, ion channels and neurotransmitter transporters, and did not interact with the human ether-a-go-go-related gene (hERG) cardiac potassium channel. Compound 1 displayed analgesic activity against neuropathic pain in the capsaicin pain model (53% analgesia at 16 mg/kg), indicating that it is a sigma1 receptor antagonist. It was rapidly metabolised by rat liver microsomes. Seven metabolites were unequivocally identified; an N-debenzylated metabolite and a hydroxylated metabolite were the major products. Pooled human liver microsomes formed the same metabolites. Studies with seven recombinant cytochrome P450 isoenzymes revealed that CYP3A4 produced all the metabolites identified. The isoenzyme CYP2D6 was inhibited by 1 (IC50 88 nM) but did not produce any metabolites. CONCLUSIONS: 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] is a potent and selective sigma1 receptor antagonist, which is rapidly metabolised. Metabolically more stable sigma1 ligands could be achieved by stabilising the N-benzyl substructure.
OBJECTIVES: The pharmacology and metabolism of the potent sigma1 receptor ligand 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] were evaluated. METHODS: The compound was tested against a wide range of receptors, ion channels and neurotransmitter transporters in radioligand binding assays. Analgesic activity was evaluated using the capsaicinpain model. Metabolism by rat and human liver microsomes was investigated, and the metabolites were identified by a variety of analytical techniques. KEY FINDINGS:1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] (compound 1) is a potent sigma1 receptor ligand (Ki 1.14 nM) with extraordinarily high sigma1/sigma2 selectivity (>1100). It was selective for the sigma1 receptor over more than 60 other receptors, ion channels and neurotransmitter transporters, and did not interact with the human ether-a-go-go-related gene (hERG) cardiac potassium channel. Compound 1 displayed analgesic activity against neuropathic pain in the capsaicinpain model (53% analgesia at 16 mg/kg), indicating that it is a sigma1 receptor antagonist. It was rapidly metabolised by rat liver microsomes. Seven metabolites were unequivocally identified; an N-debenzylated metabolite and a hydroxylated metabolite were the major products. Pooled human liver microsomes formed the same metabolites. Studies with seven recombinant cytochrome P450 isoenzymes revealed that CYP3A4 produced all the metabolites identified. The isoenzyme CYP2D6 was inhibited by 1 (IC50 88 nM) but did not produce any metabolites. CONCLUSIONS:1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] is a potent and selective sigma1 receptor antagonist, which is rapidly metabolised. Metabolically more stable sigma1 ligands could be achieved by stabilising the N-benzyl substructure.