Biomedical Engineering Reference
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this is detected as an enhanced response to a i xed concentration of GABA or a leftward parallel
shift of the GABA concentration response curve.
BzRAs can, depending on their ability to shift the GABA dose response curve, be characterized
as full or partial agonists. The efi cacy (or rather maximum effect) of the BzRA is determined at a
concentration, which saturates the allosteric binding site, whereby the GABA concentration is the
determining factor.
Variation in a subunit and g subunit confer a degree of heterogeneity at the benzodiazepine bind-
ing site, and it has been possible to develop several binding-afi nity based selective BzRAs. It should
be noted however that the g2 subunit is by far the most predominant subtype and limits the selec-
tivity based on a-subtype. To date, compounds with modest a1 selectivity and a5 selectivity have
been discovered. Those with a1 selectivity appear to be more sedative in nature than nonselective
BzRAs. Since the binding site for BzRAs is allosteric in nature, it has also been possible to gener-
ate compounds with functional selectivity, behaving as agonists at one subtype but antagonists at
another. Compounds with some selectivity for a1 have been developed as hypnotic agents, such as,
zolpidem (Ambien) and zaleplon (Sonata).
By the application of molecular biology techniques, it has been possible to identify the amino acid
residues essential for the afi nity of the BzRAs. The mutation of one single amino acid (Histidine
101 to Arginine) can completely abolish benzodiazepine afi nity and this difference in pharmacol-
ogy can be observed when BzRAs are compared at a1 and a1 H101R containing GABA A recep-
tors. By introducing the a1 H101R mutation in mice, it has been possible to show that the strong
sedative effects of the unselective benzodiazepine diazepam and the a1 selective BzRA zolpidem
were strongly reduced. Furthermore, sleep studies with zolpidem in these transgenic mice strongly
indicated that the hypnotic effects of zolpidem indeed are mediated primarily via a1 containing
GABA A receptors. These types of studies are obviously very valuable for the characterization of
the contribution of different receptor populations to the overall pharmacological consequences of
a compound in vivo. However, the pharmacological consequences of a compound are a composite
of interactions with potentially several different types of receptors. In order to address the potential
for functional heterogeneity in vivo, it is necessary to obtain knowledge on exposure (CNS concen-
trations and eventually a time dependent proi le) and activity (potency and efi cacy) at the relevant
individual receptor populations. Very seldom are all these data available. However, in a recent study,
a series of compounds were systematically characterized at different human GABA A receptors,
expressed in Xenopus oocytes, by means of electrophysiology. Since most of these compounds have
been characterized clinically and BzRAs freely penetrate the blood-brain barrier (BBB), a very
good estimate of both CNS exposure and receptor activation can be obtained.
As illustrated in Figure 20.6, CNS concentrations for these compounds are well above the EC 50
values at the individual receptor combinations. A compound like indiplon in fact is used clinically at
such a high concentration that the functional selectivity is not determined by the subunit dependent
potency, but rather by the maximum response at the different receptor types. This means that the in
vitro selectivity of these compounds, which is seen at very low concentrations, is misleading when
the clinical relevant concentrations are factored in. Consequently, interpretation of in vivo data from
man or animal studies, solely based on the in vitro proi le may be highly ambiguous.
BzRAs have several serious clinical limitations. Firstly, a fading in response after long-term
treatment or tolerance. Secondly, risks for development of dependence especially over long-term
treatment, and thirdly, abuse liability. All these aspects can be addressed in preclinical studies, and
very consistently, BzRAs (irrespective of in vitro subtype selectivity) have been shown to possess
all these risk factors. However, although compounds may show development of tolerance in animal
studies, this may not be directly translatable into the clinical situation. Examples of this are the fast
acting hypnotics zolpidem and indiplon, which after long-term dosing in animals induces a down
regulation in GABA A receptors, predictable for tolerance development and withdrawal symptoms.
However, very few reports on these types of side effects are available in the clinical literature to
date, and as a consequence, the American FDA has now removed the restriction of only short term
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