MDL 26,479: a potential cognition enhancer with benzodiazepine inverse agonist‐like properties

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Abstract
1 The present study investigated biochemical, electrophysiological and behavioural properties of the novel cognition enhancer, MDL 26,479 (5-(3-fluorophenyl)-2,4,-dimethyl-3H-1,2,4-triazole-3-thione). 2 The 5-aryl-1,2,4-triazole, MDL 26,479, potently (0.22 ± 0.05 mg kg−1) inhibited [3H]-flumazenil (Ro15–1788) binding in mouse cortex but was ineffective in vitro at displacing radioligand binding to the GABAA receptor complex. 3 Parenteral administration of MDL 26,479 (1 mg kg−1) or the benzodiazepine (BZD) inverse agonist methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) (0.3 mg kg−1) increased cortical ex vivo binding of [3H]-hemicholinium-3 ([3H]-HC-3), a marker for cholinergic activation. This effect of MDL 26,479 was blocked by pretreatment with the antagonist flumazenil (1 mg kg−1). 4 MDL 26,479 (20 μm) and DMCM (1 μm) increased excitation in the hippocampal long-term potentiation (LTP) slice preparation; however, unlike DMCM, the effect of MDL 26,479 was not blocked by flumazenil. 5 In behavioural studies, MDL 26,479 did not exhibit adverse properties characteristic of drugs associated with the GABAA receptor complex. It lacked convulsant, anxiogenic, anxiolytic, or depressant effects. Since MDL 26,479 lacks activity with the BZD receptor in vitro we suggest that it acts via the GABAA receptor complex at another site on this receptor or in an as yet undefined manner or an active metabolite is formed in vivo. 6 Previous work showed that MDL 26,479 enhances learning acquisition in animal models. The present study suggests that at least some of the cognition enhancing properties are due to the enhancement of cortical and hippocampal cholinergic function and LTP.