1256269-87-0

SAK3 is a potent CaV3.1 and CaV3.3 activator. Enhances CaV3.1 and CaV3.3, but not CaV3.2 activity at concentrations of 0.01 - 10 M in neuro2A cells in vitro. Elevates ACh levels in hippocampus. Rescues impaired memory-related behaviors in OBX mice. Orally bioavailable.

SAK3 is a potent and orally active spiroimidazopyridine derivative th at enhances Cav3.1 and Cav3.3but not Cav3.2T-type voltage-gated Ca2+ channel (T-VGCC) activity (∼20% peak current increase with 0.1 nM SAK3 by whole-cell patch-clamp using human Cav3.1 or Cav3.3 transfected neuro2A; no effect up to 10 nM using Cav3.2 transfectant). Acute SAK3 oral administration (0.5 mg/kg) significantly enhances hippocampal CA1 region acetylcholine (ACh) release in na?ve miceas well as increases hippocampal ACh levels and improves memory deficits among olfactory-bulbectomized (OBX) mice. Daily SAK3 oral administration 24 hrs following hypothyroidism induction by methimazole (MMI) is efficacious against MMI-induced medial septum (MS) cholinergic neurons loss (0.5-1 mg/kg/day) and cognitive deficits (1 mg/kg/day).

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