GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA,...

TPA023 and alpha5IA are structurally related compounds that selectively modulate certain GABA(A) receptor subtypes. Hence, TPA023 has weak partial agonist efficacy at the alpha2 and alpha3 subtypes whereas alpha5IA has inverse agonist efficacy at the alpha5 subtype. These efficacy characteristics translate into novel pharmacological profiles in preclinical species with TPA023 being a nonsedating anxiolytic in rats and primates whereas alpha5IA enhanced cognition in rats but was devoid of the proconvulsant or kindling liabilities associated with nonselective inverse agonists. In vitro and in vivo metabolic studies showed that TPA023 was metabolized via CYP3A4-mediated t-butyl hydroxylation and N-deethylation whereas alpha5IA was metabolized to produce the hydroxymethyl isoxazole, the latter of which was highly insoluble and caused renal toxicity in preclinical species. In humans, TPA023 had a half-life in the region of 6-7 h whereas the half-life of alpha5IA was 2-2.5 h. TPA023 was clearly differentiated from the nonselective agonist lorazepam in terms of saccadic eye movement and unlike lorazepam, it did not impair either postural stability, as judged by body sway, or cognition. The occurrence of the hydroxymethyl isoxazole metabolite of alpha5IA in human urine precluded the use of alpha5IA in prolonged dosing studies. Nevertheless, alpha5IA was evaluated in an alcohol-induced cognitive impairment model in healthy normal volunteers and was found to reverse the memory-impairing effects of alcohol. To date, however, no efficacy data for either TPA023 or alpha5IA in patient populations has been reported, although at the very least, the preclinical and limited clinical data with TPA023 and alpha5IA validate the approach of targeting specific GABA(A) receptors through subtype-selective efficacy.