Orally available, state-dependent, potent and selective T-type calcium channel blocker (Cav3.1, Cav3.2, Cav3.3) with in vivo absence seizure-reducing efficacy.
Z944 is an orally available, state-dependent, potent and selective T-type calcium channel blocker (hCav3.1/Cav3.2/Cav3.3 IC50 by voltage clamp = 50/160/110 nM under ~30% inactivated state & 130/540/260 nM in the closed state) over non-T-type voltage-gated channels (rCaV2.2 IC50 = 11 μM/30% inactivated & 150 μM/closed; hERG/rCaV1.2/hNaV1.5 IC50 = 7.8/32/100 μM). Z944 effectively suppresses seizure activity in the GAERS (absence epilepsy rats from Strasbourg) model in vivo (10-30 mg/kg qod ip.) with no adverse cardiovascular effects or neurotoxicity.
The role of T-type calcium channels in brain diseases such as absence epilepsy and neuropathic pain has been studied extensively. However, less is known regarding the involvement of T-type channels in cognition and behavior. Prepulse inhibition (PPI) is a measure
Childhood absence epilepsy (CAE) is often comorbid with behavioral and cognitive symptoms, including impaired visual memory. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is an animal model closely resembling CAE; however, cognition in GAERS is poorly understood. Crossmodal object recognition
Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing
Molecular and cellular neurosciences, 88, 330-341 (2018-03-11)
The physiological, intrinsic activity of noradrenergic locus coeruleus (LC) neurons is important for the control of sleep/wakefulness, cognition and autonomous body functions. Dysregulations of the LC-noradrenergic network contribute to the pathogenesis of psychiatric disorders and are key findings in early
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