The in vivo properties of pagoclone in rat are most likely mediated by 5#-hydroxy pagoclone

Abstract The cyclopyrrolone pagoclone binds with roughly equivalent high affinity (0.7–9.1 nM) to the benzodiazepine binding site of human recombinant GABA A receptors containing either an α1, α2, α3 or α5 subunit. However, whereas it was a partial agonist at α1-, α2- and α5-containing GABA A receptors, pagoclone was a full agonist at receptors containing an α3 subunit. In the rat elevated plus maze assay pagoclone (3 mg/kg) had significant anxiolytic-like activity but at all three doses tested (0.3, 1 and 3 mg/kg p.o.) it produced a significant reduction in the total distance travelled. This sedative-like effect was confirmed in rat chain-pulling and spontaneous locomotor assays. Surprisingly, in the plasma and brain samples derived from the elevated plus maze assay, the major metabolite of pagoclone, 5′-hydroxy pagoclone, was present at 10–20-fold higher concentrations relative to the parent compound. In order to establish whether this metabolite might have pharmacological activity, we measured its affinity and efficacy profile and found that both were comparable to those of pagoclone with the exception that efficacy at the α1 subtype was considerably greater for 5′-hydroxy pagoclone compared with the parent. This metabolite had significant anxiolytic-like activity in the elevated plus maze but at these same doses (0.3–3 mg/kg p.o.) also produced sedation. It is therefore likely that in rats 5′-hydroxy pagoclone mediates the majority of the pharmacological actions following pagoclone administration.