Functional characterization of the antiepileptic drug candidate, padsevonil, on GABA receptors.

Objective: The antiepileptic drug candidate, padsevonil, is the first in a novel class of drugs designed to interact with both presynaptic and postsynaptic therapeutic targets: synaptic vesicle 2 proteins and γ-aminobutyric acid type A receptors (GABA Rs), respectively. Functional aspects of padsevonil at the postsynaptic target, GABA Rs, were characterized in experiments reported here.

Methods: The effect of padsevonil on GABA-mediated Cl currents was determined by patch clamp on recombinant human GABA Rs (α1β2γ2) stably expressed in a CHO-K1 cell line and on native GABA Rs in cultured rat primary cortical neurons.

Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity.

Aims: Kv1.1 (KCNA1) channels contribute to the control of neuronal excitability and have been associated with epilepsy. Kv1.

Brivaracetam differentially affects voltage-gated sodium currents without impairing sustained repetitive firing in neurons.

Aims: Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF).

Determining the relative efficacy of positive allosteric modulators of the GABAA receptor: design of a screening approach.

Gamma amino butyric acid receptors (GABA) are major therapeutic targets for the development of drugs in neurological and psychiatric disorders. The new generation of GABAA modulators is targeting subtype selectivity and low/partial efficacy on the receptor to potentially overcome the adverse effects described for drugs with full agonist profile. We evaluated a screening approach to measure the relative efficacy of GABAA positive allosteric modulators (PAM) using automated patch clamp and fluorescence membrane potential assays.