Glutamate- and GABA-based CNS therapeutics.
Glutamate- and GABA-releasing neurons form the basis for neurotransmission in the mammalian central nervous system (CNS). The co-ordination of these excitatory and inhibitory systems, together with intrinsic voltage-gated ion channels and G-protein-coupled receptor modulation, provides the diverse neuronal firing patterns, network activity and synaptic plasticity that are required for the complexity of CNS function. Virtually all of the known molecular components of the gamma-aminobutyric acid (GABA) and glutamate neurotransmitter systems have been considered as potential therapeutic targets. Positive allosteric modulators of GABAA receptors, such as the benzodiazepines, have found wide clinical use, and the N-methyl-D-aspartate receptor antagonists ketamine and memantine have therapeutic utility. In these fundamental neurotransmitter systems, drugs that provide allosteric modulation of ligand-gated ion channels or G-protein-coupled receptors, or seek to selectively target receptor subtypes, appear to hold the greatest promise for the desired balance of efficacy and tolerability. This might also be achieved through targeting transporter subtypes. A large number of compounds based on these strategies are currently in clinical trials for diseases that span a wide range of CNS disorders.
Foster
Alan C
AC
Dept of Neuroscience, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA. afoster@neurocrine.com
Kemp
John A
JA
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D002986:Clinical Trials as Topic; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018755:GABA Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018756:GABA Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018756:GABA Antagonists; D018091:Receptors, AMPA; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid