My position in Millennium is bigger than CeNeS now...
and I did not even buy very much MLNM last month.
Cen.l is why I am so glum tonight.
Oh, and the girls and beer did not show
up for the graveyard shift...
.....................Abstract View
RECOMBINANT R-TYPE AND T-TYPE CALCIUM CHANNEL INHIBITION BY LAMOTRIGINE (LTG) AND SIPATRIGINE (STG).
A.H. Hainsworth1; N.C.L. McNaughton2; A. Pereverzev3; T. Schneider3*; A.D. Randall2
1. Pharmacology/Pharmacy, De Montfort University, Leicester, United Kingdom
2. GlaxoSmithKline Ltd, Harlow, United Kingdom
3. Institute of Neurophysiology, Koln, Germany
The antiepileptic drug LTG inhibits N and P but not L-type calcium channels (Leach et al (2001) in: Levy et al (Eds), Antiepileptic Drugs, 5th Edn). The related compound STG is neuroprotective, exhibits little anti-seizure activity in animal models, and inhibits L, N, P/Q and T-type channels (Hainsworth et al (2000) CNS Drug Revs 6: 111-134; McNaughton et al (2000) Neuropharmacology 39:1247-53). The beneficial actions of LTG in absence epilepsy and Lennox-Gastaut syndrome are as yet unexplained (Leach et al 2001). As rodent studies have implicated T (1G, 1H and 1I) and R-type (1E) channels in absence epilepsy, we tested for an effect of LTG on these channel types. Rat 1G or 1I was stably expressed in HEK293 cells and whole cell Ca2+ currents recorded following voltage pulses from -90 mV to a test voltage of -25 mV (50 ms, 0.1 Hz). Human 1E and 3 were co-expressed in HEK293 cells and calcium channel currents recorded in a similar manner (test voltage: +10 mV). LTG inhibited all three channel types weakly (IC50 >> 100 M). STG inhibited 1E-mediated currents (IC50 10 M) and, as previously reported, rat 1G and 1I and human 1H-mediated currents (IC50 14 M for 1I, McNaughton et al 2000) with potency similar to that of its other actions in vitro (Hainsworth et al 2000). These data suggest that inhibition of R-type or T-type channels is not required for the anti-absence action of LTG. The significance of these channel types in the clinical profile of STG is currently unknown.
Supported by: CeNeS Ltd, Cambridge UK (AHH).
Conflict of Interest: The presenting author's laboratory has received partial financial support from CeNeS Ltd, who hold the licence for clinical trial of sipatrigine in ischaemic stroke. This might be perceived as a conflict of interest.
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