Michael John Leach

Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action.

Summary: Lamotrigine (LTG) [3,5‐diamino‐6‐(2,3‐dichlorophenyl)‐1,2,4‐triazine] is a novel anticonvulsant chemically unrelated to current antiepileptic drugs and with a pharmacological profile similar to that of phenytoin. The effect of LTG has been compared with that of phenytoin, on the release of endogenous amino acids and radiolabelled acetylcholine evoked by veratrine or potassium, from slices of rat cerebral cortex in vitro. Both veratrine and potassium evoked a marked release of glutamate and γ‐aminobutyric acid (GABA), with a more moderate release of aspartate. LTG inhibited veratrine‐evoked release of glutamate and aspartate, with ED50 values of 21 μM for both amino acids, but LTG was less potent in the inhibition of GABA release (ED50= 44 μM). At concentrations up to 300 μM, LTG had no effect on potassium‐evoked amino acid release or on spontaneous release. Also, LTG was some five times less potent in the inhibition of veratrine‐evoked [3H]acetylcholine release (ED50= 100 μM) than in glutamate or aspartate release. The total lack of effect of LTG on potassium‐evoked release and the potent effect on veratrine‐evoked release (at concentrations found in rat brain after anticonvulsant doses) strongly suggest that LTG acts at voltage‐sensitive sodium channels to stabilise neuronal membranes and inhibit transmitter release, principally glutamate. The role of glutamate in the aetiology of epilepsy is discussed.

(±)-cis-2,3-piperidine dicarboxylic acid is a partial n-methy-d-aspartate agonist in the in vitro rat cerebellar cGMP model

The effect of (+/-)-cis-2,3-piperidine dicarboxylic acid [+/-)-cis-2,3-PDA) on formation of cyclic GMP by immature (7-8 day) rat cerebellar slices has been studied. Using magnesium free medium containing the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), (+/-)-cis-2,3-PDA behaves as an NMDA partial agonist. Thus in this medium, (+/-)-cis-2,3-PDA stimulates cyclic GMP formation, an effect completely blocked by the potent, specific NMDA antagonist (+/-)-2-amino-7-phosphonoheptanoic acid [+/-)-APH) with a Ki = 17.1 microM. The production of cyclic GMP by the full agonist (+/-)-trans-2,3-PDA, was also blocked by (+/-)-APH, suggesting that in this preparation it activates NMDA receptors. (+/-)-trans-2,3-PDA was approximately half as potent as NMDA. By constructing dose response curves to NMDA in the presence of increasing concentrations of (+/-)-APH or (+/-)-APV, these compounds were shown to be competitive NMDA antagonists using Schild analysis.