THE NOVEL ANTIEPILEPTIC DRUG LEVETIRACETAM (UCB L059) APPEARS TO ACT VIA A SPECIFIC BINDING-SITE IN CNS MEMBRANES

Levetiracetam ((S)alpha-ethyl-2-oxo-pyrrolidine acetamide, ucb L059) i s a novel potential antiepileptic agent presently in clinical developm ent with unknown mechanism of action. The finding that its anticonvuls ant activity is highly stereoselective (Gower et al., 1992) led us to investigate the presence of specific binding sites for [H-3]levetirace tam in rat central nervous system (CNS). Binding assays, performed on crude membranes, revealed the existence of a reversible, saturable and stereoselective specific binding site. Results obtained in hippocampa l membranes suggest that [H-3]levetiracetam labels a single class of b inding sites (n(H) = 0.92 +/- 0.06) with modest affinity (K-d = 780 +/ - 115 nM) and with a high binding capacity (B-max = 9.1 +/- 1.2 pmol/m g protein). Similar K-d and B-max values were obtained in other brain regions (cortex, cerebellum and striatum). ucb L060, the (R) enantiome r of levetiracetam, displayed about 1000 times less affinity for these sites. The binding of [H-3]levetiracetam is confined to the synaptic plasma membranes in the central nervous system since no specific bindi ng was observed in a range of peripheral tissues including heart, kidn eys, spleen, pancreas, adrenals, lungs and liver. The commonly used an tiepileptic drugs carbamazepine, phenytoin, valproate, phenobarbital a nd clonazepam, as well as the convulsant agent t-butylbicyclophosphoro thionate (TBPS), picrotoxin and bicuculline did not displace [H-3]leve tiracetam binding. However, ethosuximide (pK(i) = 3.5+/-0.1), pentobar bital (pK(i) = 3.8+/-0.1), pentylenetetrazole (pK(i) = 4.1+/-0.1) and bemegride (pK(i) = 5.0+/-0.1) competed with [H-3]levetiracetam with pK (i) values comparable to active drug concentrations observed in vivo. Structurally related compounds, including piracetam and aniracetam, al so displaced [H-3]levetiracetam binding. (S) Stereoisomer homologues o f levetiracetam demonstrated a rank order of affinity for [H-3]levetir acetam binding in correlation with their anticonvulsant activity in th e audiogenic mouse test (r(2) = 0.84, n = 12, P<0.0001). These results support a possible role of this binding site in the anticonvulsant ac tivity of levetiracetam and substantiate the singular pharmacological profile of this compound. This site remains however to be further char acterised.