GabaA functions

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. 

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. 

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

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... 

Rudolph U, Crestani F, Mohler H (2001) GABAA recpetor subtypes dissecting their pharmacological functions. Trends Pharmacol Sci 22 188-194... 

Low K, Crestani F, Keist R, et al Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290 131-134, 2000 Luddens H, Pritchett DB, Kohler M, et al Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature 346 648—651, 1990 LupoloverY, Safran AB, Desangles D, etal Evaluation ofvisual function in healthy subjects after administration of Ro 15-1788. Eur J Clin Pharmacol 27 505-507, 1984 Maher JF, Schreiner GE, Westervelt FB Jr Acute glutethimide intoxication 1. clinical experience (twenty-two patients) compared to acute barbiturate intoxication (sixty-three patients). Am J Med 33 70-82, 1962 Marks J The Benzodiazepines Use, Overuse, Misuse, Abuse. Baltimore, MD, University Park Press, 1978... 

Meredith TJ, Ruprah M, Liddle A, et al Diagnosis and treatment of acute poisoning with volatile substances. Hum Toxicol 8 277-286, 1989 Merry J, Zachariadis N Addiction to glue sniffing. Br Med J 5317 1448, 1962 Mihic SJ Acute effects of ethanol on GABAA and glycine receptor function. Neuro-chemint 35 115-123, 1999... 

Interestingly, their function is modified by many agents that allosterieally modify GABAa reeeptor funetion (e.g. barbiturates and steroids). A further parallel with the GABAa reeeptor is that there could well be differenees in subunit eomposition of 5-HT3 reeeptors sueh that different heteromerie eomplexes form reeeptors whieh are funetionally distinet. 

Kaila, K (1994) Ionic basis of GABAa receptor channel function in the nervous system. Prog. Neurobiol. 42 489-537. 

Intracellular steroid receptors, which alter gene expression, exist for corticosteroids, oestrogens and progesterone in the brain, as in the periphery but they cannot account for the relatively rapid depression of CNS function induced by some steroids. This was explained when Harrison and Simmonds (1984) discovered that alphaxalone (the steroid anaesthetic) potentiated the duration of GABA-induced currents at the GABAa receptor in slices of rat cuneate nucleus just like the barbiturates (Fig. 13.6). Of the... 

The diversity of the GABAa subunits (Figure 3.2d) is reflected in a very complex pharmacology. Expression of the subunits in heterologous systems shows that the combinations a, (3, and y can yield functional receptors, indicating that the limitation in subunit combination is defined by expression levels and most likely cell-dependent assembly mechanisms also. The pj to p3 subunits mainly co-assemble with each other to form the GABAC receptors. 

Rudolph, U., Crestani, F., and Mohler, H., GABAa receptor subtypes dissecting their pharmacological functions. Trends Pharmacol. Sci., 22, 188-194, 2001. 

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