Seletracetam (UCB 44212) is a pyrrolidone-derived drug of the racetam family that is structurally related to levetiracetam (trade name Keppra). It was under development by UCB Pharmaceuticals as a more potent and effective anticonvulsant drug to replace levetiracetam but its development has been halted. There are two main mechanisms of action for seletracetam. The first is its high-affinity stereospecific binding to synaptic vesicle glycoprotein 2A (SV2A). Seletracetam has shown potent seizure suppression in models of acquired and genetic epilepsy, and has been well tolerated by various animal models. The second is its binding to N-type calcium channels and preventing influx of Ca2+ during high-voltage activation that is typical of epilepsy. While similar in structure to nootropic drugs, it is not expected to have cognitive enhancing properties. Seletracetam was in Phase II clinical trials under the supervision of the U.S. Food and Drug Administration (FDA) but its production is on hold.
Synthesis Seletracetam's molecular structure contains elements common to other anticonvulsants, including levetiracetam and brivaracetam, such as a nitrogen heterocyclic system. Like brivaracetam, seletracetam is a derivative of levetiracetam. Structure and activity relationship studies have concluded that the most potent anticonvulsant activity was at the amide nitrogen atom and that this activity was further enhanced by nearby electronegative functional groups such as the di-fluoro group on seletracetam.
Administration Seletracetam is an orally administered drug, after which it is quickly and efficiently absorbed. The typical dosage is 0.03–10 mg/kg per day (up to 0.6g per day).
Mechanism of action Seletracetam's anti-epileptic effects are due to its high affinity binding to synaptic vesicle glycoprotein 2A (SV2A)—part of a calcium ion regulator. The SV2A protein assists with the coordination of synaptic vesicle exocytosis, which induces neurotransmitter release in the presence of an influx in Ca2+. A correlation has been drawn between the binding affinity of seletracetam (and its analogues) to SV2A and the degree of seizure prevention in animal models. In addition, studies of ion currents have shown that seletracetam significantly decreases the amount of high-voltage derived Ca2+ currents which have been implicated in causing the high intracellular Ca2+ influx during epileptic activity. It is thought that seletracetam binds to N-type Ca2+ channels and inhibits their ability to allow calcium ions to enter the cell, although the drug does not bind to T-type channels that mediate low-voltage activated Ca2+ currents. Seletracetam thereby decreases cellular excitation, but it does not seem to affect voltage-gated Na+ or K+ currents. Selectracetam has been demonstrated to not significantly affect currents gated by NMDA, AMPA, GABA, glycine, or kainic acid. The dual effect of seletracetam is an overall decrease in the amount of Ca2+ influx in the cell during an action potential due to binding at N-type channels, which prevents over-excitation of the neuron, as well as a decrease in neurotransmitter release as a product of cellular excitation due to the interaction of the drug with SV2A, which reduces the spread of excitation to nearby cells. Compared to levetiracetam, which binds at the same site, seletracetam binds to SV2A with ten times higher affinity. The nature of why the seletracetam molecule binds so specifically to SV2A and how SV2A affects exocytosis is unclear.
Pharmacokinetics The oral bioavailability of seletracetam is >90% and its half-life is approximately 8 hours. 25% of ingested seletracetam is metabolized and excreted unchanged and about 53% is excreted in the form of an inactive carboxylic acid metabolite. The main metabolic mechanism is the hydrolysis of an acetamide to a carboxylic acid. Seletracetam exhibits first-order mono-compartmental pharmacokinetics, in which there is a simple linear relationship between the amount of drug that was administered, the time that has passed, and the amount of drug subsequently remaining in the body. This contrasts the nonlinear pharmacokinetics typical of previously available anticonvulsants such as phenobarbital, phenytolin, valproate and carbamazepine. The benefit of linear kinetics is that the steady-state concentration of the drug is directly and reliably related to the dose of the drug that is administered; this allows for simple and reliable dose adjustments.
In vitro studies In vitro studies performed in rodent hippocampal slices found that seletracetam causes a complete reversal of the increases in activity of population spike amplitude in epilepsy models. These reductions in in vitro epilepsy symptoms were present at extracellular concentrations of 3.2 μM. This is approximately 10% of the most effective concentration of levetiracetam in similar tests.
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