TTA-A2

TTA-A2 is a potent, selective and orally active t-type voltage gated calcium channel antagonist with reduced pregnane X receptor (PXR) activation. TTA-A2 is equally potent against the Cav3.1 (a 1 G) and Cav3.2 (a 1 H) channels with IC 50 values of 89 nM and 92 nM, respectively, at -80 and -100 mV holding potentials. TTA-A2 can be used for the research of a variety of human neurological diseases, including sleep disorders and epilepsy In Vitro TTA-A2 exhibits a state-dependent inhibition of α 1 I with potencies of 98 nM and 3.7 μM at membrane holding potentials of -80 and -100 mV, respectively in astandard voltage-clamp electrophysiology assay. It also exhibits excellent selectivity against the Cav1.2 (L-type), Cav2.1 (P/Q-type), Cav2.2 (N-type), and Cav2.3 (R-type) channels which all had IC 50 values of >30 μM at 80 mV. TTA-A2 exhibits high affinity in the α 1 I binding assay with a K i of 1.2 nM and has excellent selectivity over the hERG potassium channel and L-type calcium channel (both IC 50 >10 μM). MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo TTA-A2 (oral gavage; 3 mg/kg; single dose) produces significant changes in sleep architecture in rats. A reduction in active wake soon after dosing with a concurrent increase in delta sleep and decrease in REM sleep. Additionally, these effects persists for up to 4 h post-dose in rats . TTA-A2 (oral gavage; 10 mg/kg; once daily; 5 days) shows selective effect on recurrent thalamocortical network activity, it suppresses active wake and promotes slow-wave sleep in wild-type mice but not in mice lacking both Cav3.1 and Cav3.3. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Wild-type and double Cav3.1/Cav3.3 knockout C57BL6/Sv129 background micesDosage: 10 mg/kg Administration: Oral gavage; 10 mg/kg; once daily; 5 days Result: Blocked active wake and promotes slow-wave sleep in wild-type mice but not mutant mice. Form:Solid IC50& Target:IC50: 98 nM ( α 1 I at membrane holding potentials of -80 mV) IC50: 3.7 μM (α 1 I at membrane holding potentials of -100 mV)

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