TTA-A2

TTA-A2 is an inhibitor of the T-type voltage-gated calcium (Ca_v) channels (IC₅₀s = 89, 92, and 98 nM for Ca_v3.1, Ca_v3.2, and Ca_v3.3, respectively, in patch-clamp assays at -80 mV).¹ It is selective for these channels over Ca_v1.2, Ca_v2.1, Ca_v2.2, and Ca_v2.3 in patch-clamp assays (IC₅₀s = >30 µM for all at -90 mV). TTA-A2 (100 and 200 nM) reduces the viability of spheroid A549 lung cancer cells.² It decreases body weight gain and fat mass and increases lean muscle mass in mice fed a high-fat diet when administered at a dose of 10 mg/kg.³ TTA-A2 (3 mg/kg) inhibits amphetamine- or MK-801-induced locomotor activity in rats.⁴ It reduces mean pulmonary arterial pressure and right ventricle hypertrophy in a rat model of hypoxic pulmonary hypertension induced by chronic housing in a hypobaric chamber.⁵ TTA-A2 (10 mg/kg) decreases the mean time spent in active wake and rapid eye movement (REM) sleep and increases the mean time spent in delta sleep in wild-type but not Cacna1g^-/- and Cacna1i^-/- double knockout mice when administered one hour before the inactive phase.¹

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1. Kraus, R.L., Li, Y., Gregan, Y., et al. In vitro characterization of T-type calcium channel antagonist TTA-A₂ and in vivo effects on arousal in mice. J. Pharmacol. Exp. Ther. 335(2), 409-417 (2010).

2. Kumari, N., Bhargava, A., and Rath, S.N. T-type calcium channel antagonist, TTA-A₂ exhibits anti-cancer properties in 3D spheroids of A549, a lung adenocarcinoma cell line. Life Sci. 260, 118291 (2020).

3. Uebele, V.N., Gotter, A.L., Nuss, C.E., et al. Antagonism of T-type calcium channels inhibits high-fat diet-induced weight gain in mice. J. Clin. Invest. 119(6), 1659-1667 (2009).

4. Uslaner, J.M., Smith, S.M., Huszar, S.L., et al. T-type calcium channel antagonism produces antipsychotic-like effects and reduces stimulant-induced glutamate release in the nucleus accumbens of rats. Neuropharmacology 62(3), 1413-1421 (2012).

5. Chevalier, M., Gilbert, G., Roux, E., et al. T-type calcium channels are involved in hypoxic pulmonary hypertension. Cardiovasc. Res. 103(4), 597-606 (2014).