GABA_A Receptor Subtype‐Selective Efficacy: TPA023, an α2/α3 Selective Non‐sedating Anxiolytic and α5IA, an α5 Selective Cognition Enhancer

Abstract

TPA023 and α5IA are structurally related compounds that selectively modulate certain GABA A receptor subtypes. Hence, TPA023 has weak partial agonist efficacy at the α2 and α3 subtypes whereas α5IA has inverse agonist efficacy at the α5 subtype. These efficacy characteristics translate into novel pharmacological profiles in preclinical species with TPA023 being a nonsedating anxiolytic in rats and primates whereas α5IA 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 α5IA 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 α5IA 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 α5IA in human urine precluded the use of α5IA in prolonged dosing studies. Nevertheless, α5IA 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 α5IA in patient populations has been reported, although at the very least, the preclinical and limited clinical data with TPA023 and α5IA validate the approach of targeting specific GABA A receptors through subtypeselective efficacy.

Translating the frontiers of brain repair to treatments: Starting not to break the rules

“…However, studies of molecular memory systems suggest several targets for a pharmacological learning therapy in stroke. Several classes of drugs, known loosely as “cognitive enhancers”, may directly stimulate learning and memory and may be useful in stroke: AMPAKines (positive allosteric modulators of the AMPA receptor), extrasynaptic GABAα receptor antagonists, nictonic receptor subunit alpha 7 acetylcholine receptor agonists and phosphodieseterase 4 inhibitors (Barad et al, 1998; Lynch, 2006; Bitner et al, 2007; Atack, 2008). PDE4 inhibitors do modulate motor map plasticity and recovery in stroke (MacDonald et al, 2007).…”

A Randomized Clinical Trial of MK-0777 for the Treatment of Cognitive Impairments in People with Schizophrenia

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Regulation of GABAAReceptor Subunit Expression by Pharmacological Agents

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