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要旨

Caloporoside is a natural active fungal metabolite, which was isolated from Caloporous dichrous and was described to exhibit antibacterial, antifungal and phospholipase C inhibitory activity. We have previously reported evidence that related β-linked compounds, lactose and octyl-β-d-mannoside, bind and functionally modulate rodent GABA_A receptors, respectively. We have characterized the binding pharmacology of synthetic caloporoside and two further congeners, 2-hydroxy-6-{[(16R)-(β-d-mannopyranosyloxy)heptadecyl]} benzoic acid and octyl-β-d-glucoside on GABA_A receptors using a [³⁵S]-t-butylbicyclophosphoorothionate (TBPS) radioligand binding assay. Caloporoside and 2-hydroxy-6-{[(16R)-(β-d-mannopyranosyloxy)heptadecyl]} benzoic acid produced concentration-dependent complete inhibition of specific [³⁵S] TBPS binding with overall apparent IC₅₀ values of 14.7 ± 0.1 and 14.2 ± 0.1 μM, respectively. In contrast, octyl-β-d-glucoside elicited a concentration-dependent stimulation of specific [³⁵S] TBPS binding (E_mac = 144 ± 4%; EC₅₀ = 39.2 ± 22.7 nM). The level of stimulation was similar to that elicited by diazepam (E_max = 147 ± 6%; EC₅₀ = 0.8 ± 0.1 nM), and was occluded by GAB_A (0.3 μM). However, the three test compounds failed to elicit any significant effect (positive or negative) upon [³H] flunitrazepam or [³H] muscimol binding, indicating that they did not bind directly, or allosterically couple, to the benzodiazepine or agonist binding site of the GABA_A receptor, respectively. The constituent monosaccharide, glucose, and both the closely related congeners octyl-β-d-glucoside or hexyl-β-d-glucoside have no significant effect upon [³⁵S] TBPS binding. These data, together, provide strong evidence that a β-glycosidic linkage and chain length are crucial for the positive modulation of [³⁵S] TBPS binding to the GABA_A receptor by this novel chemical class.