Biomedical Engineering Reference
In-Depth Information
containing receptors. Abuse liability studies conducted by Professor Ator at Johns Hopkins School
of medicine, have indicated that the level of a2 modulation may be a primary determinant of
self-administration, suggesting that truly functionally selective a1 modulators, may be devoid of
abuse potential.
Currently no compounds with this particular pharmacological proi le have been reported, but
since several large pharmaceutical companies have conducted BzRA projects over the last 2-3
decades, these compounds may already have been synthesized.
An alternative to the full BzRAs are partial BzRAs, which in insomnia-related indications are
sufi ciently efi cacious to induce the desired induction and maintenance of sleep. As an example,
EVT-201 is active throughout the night and at the same time devoid of residual effects as measured
the next morning. The clinical advantage of partial positive allosteric modulators over full BzRAs
should in principle be a reduced risk of tolerance development, and this may be demonstrated in
preclinical studies. However, it will be important to establish these benei ts in the clinical setting.
20.3.2 M
ODULATING
S
LOW
W
AVE
S
LEEP
AND
S
LOW
W
AVE
A
CTIVITY
20.3.2.1 GABA
A
Receptor Agonists
Since the GABA receptor system is the major inhibitory neurotransmitter system in the CNS, it is
hardly surprising that GABA
A
receptor agonists and positive allosteric modulators are sedative.
However, sleep is not just a period of unconsciousness. Sleep is a very dynamic process with a
large degree of ongoing neuronal general and unspecii c dampening of neuronal activity. Therefore,
sleep-enhancing agents will act somewhat differently to anesthetics, which produce unconscious-
ness combined with insensitivity to external stimuli and often combined with analgesia. Hence
anesthetics like propofol and etomidate do not induce sleep, but rather nonrousable unconscious-
ness. While these are very different processes, it is now clear that anesthetics act at least in part
through sleep-inducing pathways, and do not just produce a general dampening effect throughout
the CNS. Further work will further differentiate these processes.
Quite surprisingly, GABA
A
receptor agonists appear to affect sleep in a very particular manner.
Studies by Lancel and coworkers and later by Winsky-Sommerer and Tobler have demonstrated
that muscimol and gaboxadol (Figure 20.7) specii cally modulate sleep stages in a manner, which
is highly dependent on particular receptor populations. Gaboxadol and muscimol which both pen-
etrates the BBB are functionally selective for the extra-synaptically located d-subunit containing
GABA
A
receptors (non-g containing receptors, which are insensitive to modulation by BzRAs; see
Figure 20.5). This functional selectivity for extra-synaptic receptors is in fact shared by all GABA
A
receptor agonists. However, since gaboxadol and muscimol readily penetrates the BBB, only these
compounds have been characterized using in vivo studies.
Binding afi nity using a radiolabeled agonist for the GABA binding site demonstrates little in
the way of subtype selectivity for a variety of agonists and subtypes. This is understandable since
the agonist binding site, which is located at the interface between a and b subunits remains con-
served across all receptor subunits characterized so far. The functional consequences of receptor
activation, however, are highly dependent on the receptor subunit composition. As illustrated in
Figure 20.8, the potency and relative maximum response of gaboxadol cover the ranges from low
OH
OH
O
HN
H
2
N
H
2
N
N
N
OH
O
O
GABA
Gaboxadol
Muscimol
FIGURE 20.7
Structures of GABA, gaboxadol, and muscimol.
