Released GABA is actively taken back into the GABAergic neurons or glial cells in the brain by GABA transporters (GATs).28,34 Tiagabine, structurally related to nipecotic acid, is a selective inhibitor of the neuronal and glial GAT1 at the GABAergic neurons and an effective drug for the treatment of patients with refractory epilepsy.34 Addition of two lipophilic heterocyclic rings to the nicopetic acid moiety did not interfere with its ability to bind GAT1 but actually allows tiagabine to cross into the brain freely and also more selectively than nicopetic acid toward GAT1.34
DRUGS THAT BIND TO THE GABAa RECEPTOR COMPLEX AND MODULATE CHLORIDE INFLUX
Many clinically useful anxiolytic hypnotic-sedatives and some AED drugs such as BZDs, and barbiturates (e.g., phenobarbital) exert their pharmacological actions by interacting with a discrete neuronal site on the GABAA- BZD receptor-chloride channel complex.35 The GABAA-chloride ionophore is a glycoprotein pentamer that contains two a, two 3, and one y subunit and is present throughout the mammalian brain.28,35 It has been hypothesized that binding of BZD agonists such as clonazepam to its receptor enhances GABA-mediated inhibitory neurotransmission by increasing the frequency of chloride channel openings. TPM, a broad-spectrum AED, also binds and increases the frequency of chloride channel opening but at a different site than the BZDs.18 Barbiturates, on the other hand, bind to a third binding site on the GABAa receptor complex and increases the duration of chloride channel openings.35 It has been hypothesized that the binding of these drugs to their respective binding sites induces conformational changes, thereby allowing GABA to work more efficiently to modulate chloride channel openings.
Excitatory Glutamate-Mediated Receptors as Target for Anticonvulsants
The acidic amino acids, L-glutamate and L-aspartate, are the most important excitatory neurotransmitters in the brain acting through two distinct families of glutamate receptors, the ligand-gated, ionotropic receptors and the G-protein-coupled metabotropic receptors.36 The ligand-gated glutamate receptors such as N-methyl-D-aspartic acid (NMDA)/a-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptors modulate sodium and calcium influx and are involved in mediating excitatory synaptic transmission including the initiation and spread of seizure activity. Activation of these receptors is responsible for important functions in the brain including long-term potentiation in memory acquisition, learning, and some neurodegenerative disorders.22,37 These receptors are potential therapeutic targets for epilepsy and other neurodegenerative disorders such as stroke and head injury, Alzheimer, and other chronic debilitating disorders. However, efforts in finding effective and safe NMDA antagonists have failed because of their toxicities and intolerable side effects.38 Thus, with the exception of TPM, which deriving some of its antiepileptic action by modulating the AMPA receptor and FBM, which appears to bind to the glycine binding site on the NMDA receptor, none of the current AEDs has any direct action at the postsynaptic glutamate receptors.19 Metabotropic glutamate receptors, on the other hand, modulate the release of glutamic acid, GABA, and other important neurotransmitters in the brain. Thus, these receptors are exciting new therapeutic targets for designing medications for pain, addiction, Parkinson disease, schizophrenia, and other neurodegenerative disorders.28
Was this article helpful?