TP-003

TP-003 is a positive allosteric modulator of the GABA_A receptor (GABA_AR).¹ It potentiates GABA-induced currents in HEK293 cells expressing α₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, or α₅β₂γ₂ subunit-containing GABA_ARs (EC₅₀s = 20.3, 10.6, 3.2, and 5.6 nM, respectively). TP-003 (10 mg/kg) increases the number of entries into, and the time spent in, the open arms of the elevated plus maze in triple point-mutated mice in which only GABA_ARs containing the α₂ subunit are sensitive at the benzodiazepine (BDZ) site but not in mice with wild-type GABA_ARs or mice expressing only α₃-BDZ-sensitive GABA_ARs. It also increases locomotor activity in mice expressing only α₂-BDZ-sensitive GABA_ARs when administered at a dose of 3 mg/kg but reduces locomotor activity in mice expressing only α₁-BDZ-sensitive GABA_ARs at 3, 10, and 30 mg/kg. TP-003 (10 mg/kg) induces muscle relaxation in mice expressing only α₃-BDZ-sensitive GABA_ARs but not those expressing α₂-BDZ-sensitive GABA_ARs.

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1. Neumann, E., Ralvenius, W.T., Acuña, M.A., et al. TP003 is a non-selective benzodiazepine site agonist that induces anxiolysis via α2GABAA receptors. Neuropharmacology 143, 71-78 (2018).