GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer

Abstract

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.

Figure 1

Origins of TPA023 and α5IA. Both compounds were derived from a common ancestor (3‐Phenyl‐6‐(2‐pyridyl)methyloxy‐7,8,9,10‐tetrahydro‐(7,10‐ethano)‐1,2,4‐triazolo[3,4‐a]phthalazine; Compound 62, Carling et al. 2004; Compound 3, Carling et al. 2005; Compound 1, Russell et al. 2005) and entailed systematic replacements of the 2.2.2 bicyclic group (replaced with a t‐butyl group at the 7‐position in L‐838417 and TPA023 or a benzo fused ring structure in α5IA), the pendant phenyl at the 3‐position (2‐fluorophenyl in TPA023 and 3‐methyl isoxazole in α5IA), and the O‐linked group at the 6‐position (2‐ethyl‐1,2,4 triazole in TPA023 and 1‐methyl‐1,2,3 triazole in α5IA).

Figure 2

Affinity and efficacy of TPA023 and α5IA at recombinant human GABA_A receptors containing β3, γ2 and either an α1, α2, α3, or α5 subunit stably expressed in mouse fibroblast cells. Affinity was measured using a [³H]flumazenil radioligand binding assay under equilibrium conditions whereas efficacy was measured using whole‐cell patch clamp electrophysiology with the extent of the modulation of a GABA EC₂₀‐equivalent concentration being expressed relative to that observed with the nonselective full agonist chlordiazepoxide in the case of the GABA‐induced currents being potentiated (i.e., agonism) or the non‐selective full inverse agonist DMCM when GABA‐induced currents were attenuated (i.e., inverse agonism). (Data modified from Atack et al. 2006c and Dawson et al. 2006.)

Figure 3

The major metabolic pathways of TPA023 and α5IA. Metabolism of TPA023 proceeds via the predominantly CYP3A4‐mediated t‐butyl hydroxylation and N‐deethylation (Ma et al. 2007) whereas the single major metabolite of α5IA is the hydroxymethyl isoxazole.

Figure 4

Plasma pharmacokinetics of TPA023 and α5IA in man. A. Plasma TPA023 concentrations were measured after single doses of 0.5, 1.5, or 3.0 mg of an immediate release formulation. Data were collected from two separate studies, one of which was a pharmacodynamic study (0.5 and 1.5 mg doses; de Haas et al. 2007) and the other was a metabolism and disposition study (3 mg dose; Polsky‐Fisher et al. 2006). Data represent mean (n= 12 for the 0.5 and 1.5 mg doses and n= 5 for the 3.0 mg dose). B. Plasma concentrations of α5IA and the hydroxymethyl isoxazole M1 metabolite following a single dose of 8 mg α5IA. Data are the mean (n= 12; Xue et al. 2004). (Data redrawn from Xue et al. 2004; Polsky‐Fisher et al. 2006 and de Haas et al. 2007.)

Figure 5

α5IA reduces the ethanol‐induced impairment on word recall. Twelve male volunteers (mean age 24) were given either α5IA (4 mg) or placebo 2 h prior to being given alcohol in the form of vodka at a dose of 0.8 g/kg during a 0.5‐h period. One‐hour later they were asked to memorize a list of 20 words and 0.5 h later (i.e., 4 h after placebo or α5IA administration) were asked to write down as many words from that list as they could recall. Values shown are mean ± SEM. (n= 12). ***, P < 0.001.