Selective, Orally Active γ-Aminobutyric Acid_A α5 Receptor Inverse Agonists as Cognition Enhancers

Abstract

Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.

An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition

“…Based upon its preferential hippocampal location, it was hypothesized that a compound with inverse agonism selective for ␣5-containing GABA A receptors might enhance hippocampally mediated cognitive function (Maubach, 2003) and accordingly such a compound, ␣5IA, was identified (Sternfeld et al, 2004). We now show that in rodents this compound not only enhances the performance in a hippocampus-dependent cognitive test but also is devoid of anxiogeniclike behavior and convulsant, proconvulsant, kindling, or motor-impairing activities.…”

“…, methyl-6,7-dimethoxy-4-ethyl-␤-carboline-3-carboxylate (DMCM), diazepam, and flumazenil (Ro 15-1788) were purchased from SigmaAldrich (Gillingham, UK), and bretazenil was a gift from F. Hoffman-La Roche (Basel, Switzerland (Fig. 1) was synthesized as described previously (Sternfeld et al, 2004).…”

Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance

“…Two structurally similar triazolophthalazines, α 5 IA and α 5 IA-II (Table 1, 2), were also developed to be orally bioavailable and selective for α 5 GABA A Rs. These negative allosteric modulators that bind at the benzodiazepine site enhanced the performance of rodents in the DMTP water maze test without showing anxiogenic, sedative or convulsant effects [41,[45][46][47].…”

“…One compound of this class, Compound 43 ( Table 1, 2), enhanced the cognitive performance of rats in the delayed matching-to-position (DMTP) version of the Morris water maze model without the anxiogenic or convulsive side effects typical of non-selective benzodiazepine receptor inverse agonists such as methyl-6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) [39][40][41][42]. A similar result was observed with an orally administered α 5 GABA A R-selective pyrazolotriazine compound, MRK-016 (Table 1, 2), although this drug was discontinued because it was poorly tolerated in elderly subjects and exhibited unpredictable pharmacokinetics [43,44].…”

“…This was exacerbated by renal toxicity resulting from the accumulation of crystalline metabolites in the kidney [46]. Although both triazolophthalazines were devoid of convulsant side effects, α 5 IA-II, but not α 5 IA, was found to possess proconvulsant efficacy at high receptor occupancy owing to an observed potentiating effect on pentylenetetrazole-induced seizures in mice [41].…”