Biomedical Engineering Reference
In-Depth Information
R
OH
N
O
HN
15.32a-d
R =
FIGURE 15.7
A superimposition of the proposed bioactive conformations of muscimol (
15.22
, green carbon
atoms) and 4-PIOL (
15.26
, gray carbon atoms) binding to two different conformations of an arginine residue
at the orthosteric-binding site. A series of 4-substituted 4-PIOL compounds (
15.32a-d
) are included illustrat-
ing the large space spanned by the 4-substituents. The tetrahedrons indicate receptor excluded volumes.
The overall molecular architecture of the orthosteric sites at the GABA
A
and GABA
C
receptors
appear to be quite similar as most GABA
A
agonists display some agonist/antagonist activities at
GABA
C
receptors as well. THIP (
15.23
), the standard GABA
A
agonist, has been shown to be a
partial agonist at GABA
A
receptors and a competitive antagonist at GABA
C
receptors. Likewise,
the GABA
A
agonists muscimol (
15.22
), isoguvacine (
15.27
), and imidazol-4-acetic acid (IAA
[
15.28
]) act as partial GABA
C
agonists. However the fact that GABA
A
and GABA
C
receptors
exhibit distinct antagonist proi les clearly indicates that orthosteric sites of these receptors are
not identical.
Upregulation of GABA activity would, in general, be benei cial in various conditions including
epilepsy, pain, anxiety, and insomnia. Direct activation of the ionotropic GABA receptors using
GABA
A
agonists has for long not been anticipated as a useful therapeutic approach due to desensiti-
zation of the receptors. However, the GABA
A
agonist THIP has proven to be a potential drug in the
treatment of insomnia (see Chapter 20).
15.5.3 M
ODULATORY
A
GENTS
FOR
THE
GABA
A
R
ECEPTOR
C
OMPLEX
The GABA
A
receptor complex is the target for a large number of structurally diverse compounds,
some of which are pharmacologically active and used clinically. These compounds include BZD,
ethanol, general anesthetics, barbiturates, and neuroactive steroids, all of which act via a wide range
of distinct allosteric-binding sites within the pentameric receptor complex.
The allosteric modulators exert their effects by binding to the GABA
A
receptor complex and
affect GABA-gated chloride conductance. This modulation only takes place when GABA is present
in the synaptic cleft, which could be preferable rather than a general receptor activation by exposure
to a GABA agonist. Compounds within this group of modulators are marketed for the treatment of
anxiety, epilepsy, insomnia, muscle relaxation, and anesthesia. Preclinical studies are going on with
the focus on cognitive enhancement and schizophrenia as well.
The fact that receptor regions targeted by allosteric ligands typically are less conserved than the
orthosteric sites, in general, opens up for development of subtype-selective modulators with more
specii c pathophysiological effects and reduced side effects.
