Saturday, May 9, 2015

Brivaracetam | SV2A Protein Modulators| Sodium Channel Antagonists | Treatment for Partial-Onset Seizures

Brivaracetam {[2S]-2-[(4R)-2-oxo-4-propylpyrrolidinyl] butanamide} is a 2-pyrrolidone derivative with high affinity for synaptic vesicle glycoprotein 2a (SV2A). It is the newest member of UCB’s family of racetam compounds, and chemically is a 4-n-propyl analogue of its predecessor Levetiracetam [1]. Brivaracetam is a highly selective, reversible and water soluble SV2A ligand.
The birth of Brivaracetam is credited to the discovery of synaptic vesicle protein 2A (SV2A) as the principal site involved in the antiepileptic effect of Levetiracetam. This stimulated UCB to search for analogues with higher affinity for SV2A than Levetiracetam. While the exact role of SV2A is unknown, there is a high correlation between binding affinity at SV2A and antiepileptic activity [1, 2].
Brivaracetam: 2D and 3D Structure. There is a possibility of intramolecular hydrogen bond.
Brivaracetam was identified after a primary in vitro screening of over 10000 compounds, a secondary screening of 900 compounds in the mouse audiogenic seizure model, and a tertiary screening of 30 drug candidates in various other epilepsy models [2].
Brivaracetam has been extensively evaluated and compared to levetiracetam in a wide variety of in vitro and in vivo preclinical models of seizures and epilepsy. This assessment has demonstrated that brivaracetam exerts a more potent seizure protection than levetiracetam and, in several models, complete seizure suppression.
Brivaracetam binds to SV2A in the brain (pKi = 7.1) with greater selectivity and 15- to 30-fold higher affinity than Levetiracetam (pKi = 6.1), as demonstrated in preclinical models, and has demonstrated efficacy in reducing the frequency of partial onset seizures in clinical trials.
Since Brivaracetam is differentiated from Levetiracetam not only in potency but also in efficacy in several preclinical models of epilepsy, it has been postulated that either additional mechanisms of action for Brivaracetam might exist besides binding to SV2A, or alternatively that the binding of Brivaracetam to SV2A might lead to a qualitatively different functional response. The compound has been found to possess some inhibitory activity at neuronal voltage dependent sodium channels (albeit at high concentrations), on which Levetiracetam is inactive, and to reverse the inhibitory effects of a number of negative allosteric modulators, such as zinc and β-carbolines, on γ-aminobutyric acid (GABA)- and glycinegated currents [3].
Oral Brivaracetam has been approved in the EU on 14 Jan 2016 and by US FDA on 18 Feb 2016, as an adjunctive treatment for partial-onset seizures with or without secondary generalization (spreading to both sides of the brain after the initial seizure) in patients aged 16 or more years.

Epilepsy: Causes, Treatments and SV2A
Epilepsy, a common neurological disorder characterized by recurrent spontaneous seizures, is a major health problem that affects 1% of the population worldwide. Despite progress in understanding the pathogenesis of epileptic seizures, the cellular basis of human epilepsy remains a mystery and, in the absence of specific etiological comprehension, approaches to drug therapy are still directed toward the control of symptoms, i.e., suppression of seizures. Chronic administration of antiepileptic drugs (AEDs) is the treatment of choice in epilepsy. The goal of current therapy with an AED is to keep the patient free of seizures without inducing significant adverse effects [4].
Synaptic vesicle protein 2 (SV2) is an integral transmembrane glycoprotein expressed in neurons and endocrine cells. In neurons, SV2 is localized to synaptic vesicles and has been proposed to function as a modulator of Ca2+-dependent neurotransmitter release.
SV2 has three isoforms, A, B, and C, with SV2A being the most widely expressed in the brain. Of the three known isoforms, SV2A is ubiquitously expressed in the rat brain, whereas SV2B, although widely expressed, is undetectable in several groups of neurons in the hippocampus, central gray nuclei, and cerebellum. SV2C has a much more restricted distribution being found mostly in the basal ganglia, midbrain, and brainstem [5].
The exact function of SV2A, however, still remains elusive. SV2A was identified as the specific binding site for Levetiracetam, a second generation antiepileptic drug. Levetiracetam reduces presynaptic glutamate release particularly in neurons with a sustained and high frequency firing, and it was shown that the antiepileptic efficacy of Levetiracetam and its derivatives correlates with their binding affinity to SV2A.
Recently it was proved that human SV2A, when expressed in yeast, functions as a galactose transporter. Moreover, the antiepileptic drug Levetiracetam, which specifically binds to SV2A inhibits the galactose-dependent growth of SV2A-expressing yeast cells [5].

Brivaracetam Activity in Experimental Models of Seizure and Epilepsy
In in vitro models of epileptic activity in rat hippocampal slices, Brivaracetam (1-10 µM) inhibited epileptiform responses induced by a high potassium/low calcium ions perfusion fluid or by addition of 5 µM bicuculline methiodide (BMI) to the normal perfusion liquid. In particular, Brivaracetam (3.2 µM) reduced the occurrence of spontaneous bursts, while Levetiracetam (32 µM) was inactive against spontaneous bursts [1].
Brivaracetam shows potent activity in many in vivo models of seizures and epilepsy. For example:
a: Unlike Levetiracetam, Brivaracetam is effective in inhibiting seizures induced in the classical maximal electroshock and pentylenetetrazole seizure tests, albeit at relatively high doses.
b: Audiogenic seizure-susceptible mice were better protected against clonic convulsions induced by acoustic stimuli when treated with Brivaracetam than with levetiracetam [ED50 values = 2.4 versus 30 mg/kg, intraperitoneally (i.p.)].
d: In corneally kindled mice (3 mA, 3 s, twice daily), Brivaracetam provided more potent protection than Levetiracetam against secondarily generalized motor seizures (ED50 = 1.2 versus 7.3 mg/kg, i.p.). In the corneal kindling development model, pretreatment of mice twice daily with Brivaracetam (0.21-6.8 mg/kg, i.p.) prior to corneal stimulation (3 mA, 3 s, twice daily) also resulted in a more potent and persistent inhibition of kindling development than observed with Levetiracetam.
e: In hippocampal-kindled rats, a model of localization-related epilepsy, brivaracetam provided more potent protection against seizures than levetiracetam (minimal active dose = 0.21 versus 54 mg/kg, oral).
The activity profile of Brivaracetam in these models is suggestive of broad-spectrum efficacy against partial and generalized seizure types [1].

Dosages and Approvals:
Brivaracetam (Tradename: Briviact) is discovered and developed at UCB Pharma, which has a history of launching racetam derivatives having anticonvulsant (antiepileptic) properties. Brivaracetam is available as tablets (10, 25, 50, 75 and 100 mg), an oral solution (10 mg/ml) and a solution for injection or infusion (drip) into a vein (10 mg/ml). The recommended starting dose is either 25 mg twice a day or 50 mg twice a day, depending on the patient’s condition. The dose can then be adjusted according to the patient’s needs up to a maximum of 100 mg twice a day. Briviact can be given by injection or by infusion (drip) into a vein if it cannot be given by mouth [6].

Reported Activities for Brivaracetam:
The affinity of Brivaracetam for rat SV2A (80 nM) was about 15 fold higher than that of Levetiracetam (1250 nM) and this was further confirmed in human cerebral cortex with affinity values for Brivaracetam and Levetiracetam of 50 nM and 1585 nM respectively. The binding affinity (pKi) for human synaptic vesicle protein 2A (hSV2A) of Brivaracetam was 7.1; as compared to 6.1 for Levetiracetam [1].
Brivaracetam inhibited voltage-gated sodium channel currents (IC50 = 7 uM) as compared to Levetiracetam, which was inactive even at up to 1 mM in the same assay. Reversal of the activity was seen in high voltage activated calcium channel currents, where Levetiracetam has an IC50 value of 13.9 uM; and Brivaracetam was inactive even at 1 mM.
Brivaracetam was profiled at 10 µM (a concentration greater than100 fold higher than its affinity for SV2A) against a panel of more than 55 targets comprising receptors, enzymes, ion channels and transporters. This panel included targets potentially involved in epilepsy such as GABAA (GABA and benzodiazepine binding sites), glycine, kainate, AMPA and NMDA receptors, L-type and N-type calcium channels, ATP and voltage dependent potassium channels, tetrodotoxin sensitive sodium channels, GABA transporter, glutamic acid decarboxylase (GAD) and the ryanodine receptor. Other targets screened were mostly G-protein coupled receptors (subtypes of adenosine, adrenergic, canabinoid, dopamine, histamine, opioid, muscarinic, neurokinine and serotonine receptors), transporters (adenosine, noradrenaline, dopamine and GABA) and enzymes (acetylcholinesterase, monoamine oxidase A and B). Brivaracetam did not bind, inhibit or activate any of the aforementioned targets.
Saturation curves indicated that [3H]ucb 34714 binds to an homogenous population of binding sites that have the characteristics of SV2A. Results from SV2A KO mice indisputably showed that [3H]ucb 34714, at concentrations up to 600 nM (the highest concentration tested) only labels SV2A proteins, as no specific binding for [3H]ucb 34714 could be observed in the brains of SV2A-/- KO mice [3].
Activities for Brivaracetam
 pKi (Binding affinity for S2VA(h)) = 7.1
IC50 (Inhibition of voltage-gated sodium channel currents) = 7 uM

Common name: UCB-34714; UCB 34714; UCB34714; Brivaracetam; Rikelta
Trademarks: Briviact
Molecular Formula: C11H20N2O2
CAS Registry Number: 357336-20-0
CAS Name: (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide
Molecular Weight: 212.15
InChI: InChI=1S/C11H20N2O2/c1-3-5-8-6-10(14)13(7-8)9(4-2)11(12)15/h8-9H,3-7H2,1-2H3,(H2,12,15)/t8-,9+/m1/s1
Mechanism of Action: SV2A Protein Modulators; Sodium Channel Antagonists
Activity: Antiepileptic drugs; Neuroprotectants; Non-opioid Aanalgesics; Nootropics; Treatment for Partial-Onset Seizures
Status: Launched 2016 (US, EU)
Chemical Class: Pyrrolidinones; Amides; Small-molecules; Racetam Compounds
Originator: UCB Pharma
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