GabaA

GABAA receptor antagonist fiYPNOTICS, SEDATIVES, ANTICONVULSANTS, AND ANXIOLYTICS] (Vol 13) Bicyclo[2.2.1]heptan-2-one [497-38-1]... 

Krogsgaard-Larsen and co-workers have protected the P-keto functionality as a ketal as a modification to the traditional conditions so attack of hydroxylamine is directed towards the ester. They prepared hydroxamic acid 10 from ester 9 then cyclized with sulfuric acid to isoxazole 11, in route to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a selective GABAa receptor agonist studied clinically for insomnia. 

Krogsgaard-Larsen and co-workers continued to utilize Claisen isoxazole chemistry in the preparation of GABAa receptor antagonists reported in 2000. In the synthesis of protected 3-isoxazolols 17a-f, P-oxoesters 16a-f were cyclized at -30°C followed by heating with concentrated hydrochloric acid at 80°C. 

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

GABAa receptors that contain the al, a2, a3, and a5 subunits in combination with (3 and y subunits can bind classical benzodiazepines, e.g., diazepam, whereas GABAa receptors that contain the a4 and a6 subunits do not bind classical benzodiazepines. Essentially, all benzodiazepines that are currently in clinical use bind indiscriminately to GABAa receptors that contain the... 

Benzodiazepines. Figure 3 Dissection of benzodiazepine pharmacology. The functional roles of GABAa receptor subtypes, mediating particular actions of diazepam, are indicated. A sign indicates that the respective response is mediated by the respective receptor subtype, a sign indicates that the respective response is apparently not mediated by the respective receptor subtype. ND = not determined. 

Although flumazenil binds with high affinity to the benzodiazepine site of GABAa receptors, it has practically no action when given alone. However, flumazenil competitively blocks the action of benzodiazepine site agonists. Flumazenil can be used to terminate the action of benzodiazepines, e.g., after a benzodiazepine overdose. It may also serve as a diagnostic tool in this regard. 

The definition of desired therapeutic and side effects in the case of the benzodiazepines very much depends on the clinical problem in question. The sedative and hypnotic actions are desired effects in the treatment of insomnia, but undesired effects in the treatment of anxiety disorders. Effects that are usually undesired include daytime drowsiness, potentiation of the sedative effects of ethanol, and anterograde amnesia. They are mediated via the benzodiazepine site of GABAa receptors, since they can be antagonized with flumazenil. 

Crestani F, Keist R, Fritschy J-M et al (2002) Trace fear conditioning involves hippocampal a5 GABAa receptors. Proc Natl Acad Sci USA 13 8980—8985... 

McKernan RM, Rosahl TW, Reynolds DS et al (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAa receptor al subtype. Nat Neurosci 3 587-592... 

Mohler H (2007) Molecular regulation of cognitive functions and developmental plasticity impact of GABAa receptors. Neurochem 102 1-12... 

Tobler I, Kopp C, Deboer T et al (2001) Diazepam-induced changes in sleep role of the al GABAa receptor subtype. Proc Natl Acad Sci USA 98 6464 6469... 

Bicuculline is a competitive antagonist at the GABAa receptor. It is a plant alkaloid. 

The benzodiazepine, lorazepam, acts allosterically on GABAa receptors to facilitate the actions of GABA. Lorazepam has some antiemetic activity in cancer chemotherapy. When used in combination therapy, it does not appear to add to antiemetic control but may contribute to a reduction in anxiety. 

In an attempt to visualize the site of action of ethanol, tryptophan mutation at position S270, TM2 and TM3 domains of the GABAa a2 subunit were modeled as antiparallel a-helices. The model showed that the region between S270 TM2 and TM3 contains a small cavity that may not be filled by side chains of adjoining helices. In contrast, the model of the S270W mutation demonstrated that the side chain of tryptophan completely occupied this cavity, which could eliminate occupation of the putative cavity by ethanol. 

These findings were unexpected because previous studies had demonstrated that the y2 subunit is required for potentiation of GABAa receptor function by low concentrations of ethanol [2]. The y2 subunit gene is located within a definitely mapped quantitative trait locus (QTL) for acute alcohol withdrawal on mouse chromosome 11 [1]. Allelic variation was genetically... 

Harris RA, Blednov Y, Findlay G et al (2001) Can a single binding site account for actions of alcohols on GABAa and glycine receptors Alcohol Clin Exp Res (5 Suppl) 79S-80S... 

GABAa receptors are pentameric complexes on the postsynaptic membrane with a central pore with selectivity for chloride ions. Benzodiazepines and barbiturates increase the GABA-induced chloride currents, leading to hyperpolarization of the postsynaptic membrane. 

The binding site for barbiturates on the GABAa receptor is less well defined. Barbiturates act by increasing the conductance level. In contrast to benzodiazepines, they also display direct agonistic action on GABAa receptors. Also in contrast to... 

Neurosteroids prolong the mean open time of recombinant GABAa receptor channels. Whereas, at least in recombinant systems, the identity of the a and (3 subunits has little or no effect on neurosteroid action, substitution of the y subunit by a 8 subunit suppresses the GABA-modulatory activity of the neurosteroids. 

---