GABA-A receptor ligands

Ebert, B., Storustovu, S., Mortensen, M., and Frplund, B. (2002) Characterization of GABA(A) receptor ligands in the rat cortical wedge preparation evidence for action at extrasynaptic receptors Br. J. Pharmacol. 137,1-8. 

GABA-A receptor ligands GABA uptake inhibitors... 

Marder M, Paladini AC. 2002. GABA(A)-receptor ligands of flavonoid structure. Curr Top Med Chem 2 853-867. 

Schofield, PR, Darlison, MG, Fujita, N, Burt, DR, Stephenson, FA, Rodriguez, H, Rhee, LM, Ramachandran, J, Reale, V, Glencorse, TA et al. (1987) Sequence and functional expression of the GABA A receptor shows a ligand-gated receptor super-family. Nature 328 221-227. 

Basile AS, Gammal SH, Jones EA, Skolnick P GABA-A receptor complex in an experimental model of hepatic encephalopathy Evidence for elevated levels of an endogenous benzodiazepine receptor complex ligand. J Neurochem 1989 53 1057-1063. 

Ebert, B., Mortensen, M., Thompson, S. A., Kehler, J., Wafford, K. A., and Krogsgaard-Larsen, P. (2001) Bioisosteric determinants for subtype selectivity of ligands for het-eromeric GABA(A) receptors. Bioorg. Med. Chem. Lett. 11, 1573-1577. 

Ion channels (center). These receptors contain ligand-gated ion channels. Binding of the signaling substance opens the channels for ions such as Na, Ca, and Cl . This mechanism is mainly used by neurotransmitters such as acetylcholine (nicotinic receptor see p.224) and GABA (A receptor see p.354). 

Ligand-gated ion channel proteins (e.g., GABA-A receptor)... 

There are two main families of ligand-gated ion channel proteins that act as ionotropic receptors. One family includes the nicotinic acetylcholine receptor, the GABA-A receptor, the glycine receptor, and a class of serotonin receptor. The other family comprises various types of ionotropic glutamate receptors. Since these various ligand gated ion channels are activated by neurotransmitters, the medicinal chemistry of these proteins is presented in detail in chapter 4. 

Two types of receptor have been identified, termed Bzl and Bz2. These receptors occupy different sub-units of the GABA-A receptor and therefore have different affinities for the benzodiazepine ligands. For example, the potent hypnotic zolpidem binds to the Bzl receptor that is linked to the alpha-1 site on the GABA-A receptor while the hypnotic zopiclone binds to the Bz2 receptor which occupies both the alpha-2 and 3 sites on the GABA receptor. This selectivity for the Bzl receptor may account for the fewer side effects of zolpiden in comparison to other hypnotic benzodiazepines. 

Another possibility that may account for an increase or decrease in the anxiety state relates to the presence of endogenous ligands that act on the benzodiazepine receptors. These ligands have been called endozepines and although a number of compounds have been isolated from mammalian brain it is uncertain whether the endogenous concentration is sufficiently high for them to modulate GABA-A receptor or benzodiazepine receptor function. 

In SUMMARY, the naturally occurring ligands for the benzodiazepine and /or GABA-A receptor sites that act as sedative-hypnotics or anxiolytics all directly or indirectly augment GABA-A receptors and thereby depress neuronal activity. In this respect they act in a similar way to the various classes of drugs used to treat anxiety and insomnia. Such compounds do not induce natural sleep. They all increase slow-wave sleep but reduce REM sleep. 

Szabo, S. T. Blier, P. (2001a). Serotonin (1A) receptor ligands act on norepinephrine neuron firing through excitatory amino acid and GABA(A) receptors A microiontophoretic study in the rat locus coeruleus. Synapse, 42, 203-212. 

The predictive models included in the program Volsurf" were utilized as part of a library designed to identify non-benzodiazepine ligands for the GABA-A receptor." A virtual library of 500 compounds was enumerated using Accord for Excel. The virtual library was filtered to remove compounds... 

Another important family of ligand gated ion channels is the receptors for the excitatory amino acid neurohansmitters such as glutamate and aspartate (Figure 10.8). These act as neurotransmitters at the vast majority of excitatory synapses in the brain. These receptors are also multisubunit ion channel arrays, in this case consisting of tehamers of related subunits (Wollmuth and Sobolevsky, 2004). The proteins that make up these subunits are all related in structure but are quite different from those that make up the nicotinic and GABA-A receptor family. 

Continued research into the identification of subtype-selective GABA /Bz receptor ligands can be expected to provide agents with more specific physiological activity. This may result in new treatments for a variety of disorders, including cognitive deficits, with decreased potential for adverse side effects. 

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