GABAa antagonists

Figure 4.1 Effect of an iontophoretic injection of bicuculline, a GABAa antagonist, on a locus coeruleus noradrenergic neuron. With reduced activity during slow wave sleep, this neuron then becomes silent during paradoxical sleep (PS). The application of bicuculline reversibly restores tonic discharge, indicating the role of GABA in the cessation of activity of this neuron during PS.

Wermuth, C. G. and Biziere, K. (1986) Pyridazinyl-GABA derivatives a new class of synthetic GABAa antagonists. Trends Pharmacol. Sci. 7,421-424. 

Epilepsy is an example of excessive neural signaling in the central nervous system. Relative cellular and extracellular space (ECS) volume has been demonstrated to play an important role in the propensity for epileptic seizures. For example, reducing ECS volume by exposure to hypotonic medium produces hyperexcitability and enhanced epileptiform activity, whereas hyperosmolar medium reduces excitability. The hypothesis that AQP4-dependent water transport in astrocytes might modulate intrinsic brain excitability was tested by seizure susceptibility in response to the GABAa antagonist convulsant pentylenetetrazol... 

A novel class of 4-arylalkyl substituted 3-isoxazole GABAa antagonists 30 has been synthesised by condensation of the appropriate p-oxo esters with hydroxylamine <02JMC2454>. 

The pronounced biological activity has rendered many substituted isoxazoles an important motif in medicinal chemistry. For instance, isoxazoles are potent and selective agonists of human cloned dopamine D4 receptors [87], they exhibit GABAa antagonist [88] analgesic, antiinflammatory, ulcerogenic [89] COX-2 inhibitory [90, 91] antinociceptive [92], and anticancer [93] activity. 

FIGURE 14.12 Affinity of GABAa antagonists for the GABAa receptor noneS (Table 14.2). 

Wermuth, C.G., Bourguignon, J.-J., Schlewer. G., Gies, J.P., Schoenfelder, A., et al. (1987) Synthesis and structure-activity relationships of a series of aminopyridazine derivatives of g-aminobutyric acid acting as selective GABAa antagonists. J. Med. Chem. 30 239-249. 

PIOL, A LOW-EFFICACY PARTIAL GABAa AGONIST SHOWING DOMINATING GABAa ANTAGONIST EFFECTS... 

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