Mechanisms of Action of Currently Prescribed and Newly Developed Antiepileptic Drugs

Clinically available antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium (Na) channels, -y-aminobutyric acid A (GABA A ) receptors, or calcium (Ca) channels. Benzodiazepines and barbiturates enhance GABA A -receptor-mediated inhibition. Phenytoin, car-bamazepine and, possibly, valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing Na channel inactivation. Ethosuximide and VPA reduce a low threshold (T-type) Ca-channel current. The mechanisms of action of recently developed AEDs are less clear. Lamotrigine may decrease sustained high-frequency repetitive firing of voltage-dependent Na action potentials, and gabapentin (GBP) appears to bind to a specific binding site in the CNS with a restricted regional distribution. However, the identity of the binding site and the mechanism of action of GBP remain uncertain. The antiepileptic effect of felbamate may involve interaction at the strychnine-insensitive glycine site of the Af-methyl-D-aspartate receptor, but the mechanism of action is not yet proven.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65554/1/j.1528-1157.1994.tb05955.x.pd

Receptor pharmacology of the antidyskinetic drug sarizotan

Objective: Sarizotan is in clinical development for levodopa-associated dyskinesia in Parkinson patients. Sarizotan was investigated for its properties at human 5HT1A, D2, D3 and D4 receptors in functional in vitro assays and on the extracellular glutamate levels in the motor cortex and the ipsilateral dorsolateral striatum by dual-probe microdialysis in awake rats. Background: In receptor binding assays, sarizotan exhibited affinity to 5HT1A, D2, D3 and D4 receptors. Besides dopamine D1, D2 and D3 receptors in the basal ganglia, 5HT1A receptors in the cortex, modulating the corticostriatal glutamate pathways, affect striatal GABA output neurons in basal ganglia circuitry. Methods: Human 5HT1A or D2-like receptors were stably expressed in CHO cells for [35S]GTPS binding assay or in AtT-20 mouse pituitary cells for measuring drug-activated G-protein-coupled inward rectifier potassium currents (GIRK; patch clamp technique) or changes in cAMP levels (stimulated with 10 M forskolin). Microdialysis probes were implanted into the motor cortex and ipsilateral dorsolateral striatum. Sarizotan was administered systemically (0.1-10 mg/kg s.c.) or included in the cortical perfusion medium (10 M) for 60 min. WAY100135 (10 M) was intracortically perfused 20 min prior to the application of sarizotan. Perfusates were collected every 20 min for 2 hours. Results: The following table summarizes the effect of sarizotan in the functional assays: Receptor Binding IC50 GTPS GIRK cAMP 5HT1A 0.1 3.5* 6.2* 1.5* D2S 17 38** 20* 0.6* D3 7 128** 5.6* 0.5* D4.2 3 30** 4.5* 0.5* D4.4 4 0.9* 5.4* 0.2* [nM]; * EC50 (Agonist) and ** IC50 (Antagonist) Dual-probe microdialysis revealed that sarizotan (s.c. or perfused into the motor cortex) produced a significant (20%-30%) reduction of cortical and striatal glutamate levels. The inhibitory effects of s.c. sarizotan on cortical and striatal glutamate levels were counteracted by intracortical perfusion with the 5HT1A receptor antagonist WAY100135. Conclusion: Sarizotan is an agonist at 5HT1A receptors and most likely also at D3 and D4 receptors, and a partial agonist at D2 receptors in functional assays. Its antidyskinetic effect may involve at least a reduction of the activity of the corticostriatal glutamate pathways with diminished activation of striatal GABA output neurons in basal ganglia circuitry

Effects of sarizotan on the corticostriatal glutamate pathways

The effects of sarizotan, a 5-HT(1A) agonist with additional affinity for D(3) and D(4) receptors, have been studied on the corticostriatal glutamate pathways using dual-probe microdialysis in the awake rat. Sarizotan given systemically (0.1-10 mg/kg s.c.) or perfused into the motor cortex (10 microM) produced 20-30% reduction of cortical and striatal glutamate levels. The inhibitory effects of the systemic sarizotan on cortical and striatal glutamate levels were counteracted by intracortical perfusion with the 5-HT(1A) antagonist WAY100135 (10 microM). These findings suggest that the anti-dyskinetic properties of sarizotan could be mediated via its 5-HT(1A) agonist actions in the motor cortex, leading to reduced activity in the corticostriatal glutamate pathways with reduced activation of the striatopallidal GABA pathway mediating motor inhibition. Synapse 58:193-199, 2005. (c) 2005 Wiley-Liss, Inc

New (sulfonyloxy)piperazinyldibenzazepines as potential atypical antipsychotics:Chemistry and pharmacological evaluation

A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M-1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities, In behavioral studies performed to indicate the potential antipsychotic efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 po for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation mo del. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS