生物活性

• 描述G protein‐gated inwardly rectifying K⁺ (K_ir3, also known as GIRK) channels modulate cell excitability, and have been implicated in a number of crucial physiological processes. ML 297 (VU 0456810) is a potent and selective GIRK1/2 (K_ir3.1/3.2) channel activator, with EC₅₀ values of 0.16 and 1.8 μM for GIRK1/2 and GIRK1/4, respectively. ML 297 is potential for the treatment of epilepsy^[1]. ML297 showed concentration-dependent efficacy when tested on cells expressing GIRK1/2 with a measured potency of ∼160 nM. In the ML297-treated (60 mg/kg) animals, there was an immediate decrease in locomotor activity compared to the control group. Furthermore, when compared to the vehicle-treated animals, the ML297-treated (60 mg/kg) group showed a modest (14%) decrease in performance on the rotarod suggesting ML297's effects on generalized locomotor activity may be mediated through sedation. In a maximal electroshock (MES) model of epilepsy in mice, ML297 (60 mg/kg) caused a robust increase in the latency of seizure onset equivalent to that observed with a 150 mg/kg dose of the known antiepileptic, sodium valproate. Moreover, ML297 (60 mg/kg) showed a highly significant ability to both prevent convulsions (p = 0.006) and prevent fatality of the PTZ (pentylenetetrazol) treatment (p = 0.001) with most of the animals treated with ML297 experiencing neither convulsions nor death^[2].