Biomedical Engineering Reference
In-Depth Information
CH 3
O
N
N
N
Cl
N
O
N(CH 3 ) 2
Diazepam ( 15.33 )
Zolpidem ( 15.34 )
FIGURE 15.8
Structures of some ligands for the benzodiazepine site.
Among the modulatory sites at the GABA A receptor complex, the BZD site is the far most studied
to date. The pharmacological proi les of ligands binding to the BZD site span the entire continuum
from full and partial agonists, through antagonists, to partial and full inverse agonists. Antagonists
do not inl uence the GABA-induced chloride l ux, but antagonizes the action of BZD agonists as
well as of inverse agonists.
With the improved knowledge of the subtypes of GABA A receptors and their inl uence on BZD
pharmacology (see Chapter 20), it has become clear that subtype-selective ligands for the modulatory
sites could provide more specii c pharmacological proi les compared to that of the traditional BZD.
Research based on this knowledge is focused on development of hypnotics (
α 1 -selective), nonsedating
α 5 -selective
inverse agonist). In spite of intensive efforts in this area unselective BZD ligands like diazepam ( 15.33 )
and a few
anxiolytics (
α 2 - and
α 3 -selective), antipsycotics (
α 3 -selective), and cognition-enhancement (
α 1 preferring ligands, including zolpidem ( 15.34 ), are still the most important BZD ligands
in the market (Figure 15.8).
15.5.4 GABA B R ECEPTOR L IGANDS
The GABA B receptors belong to the subfamily C, which also comprises the G-protein-coupled Glu
receptors (see later sections and Chapter 12). The GABA B receptors exist as heterodimers consisting
of two subunits, GABA B1 and GABA B2 . The former contains the GABA-binding domain, whereas
GABA B2 provides the G-protein-coupling mechanism. The diversity in this class of receptors arises
from the two GABA B1 splice variants, GABA B1a and GABA B1b , which together with GABA B2 form the
two physiological receptors. Activation of the G-protein-coupled receptor causes a decrease in calcium
levels, an increase in potassium membrane conductance and inhibition of cAMP formation. The result-
ing response is thus inhibitory and leads to hyperpolarization and decreased neurotransmitter release.
The GABA B receptors are selectively activated by baclofen ( 15.35 ), of which the ( R )-form is the
active enantiomer. Baclofen was developed as a liphophilic derivative of GABA, in an attempt to
enhance the blood-brain barrier penetrability of the endogenous ligand. Among the limited number
of GABA B receptor agonists, the phosphinic acid GABA bioisostere, CGP27492 ( 15.36 ), is the most
potent reported to date, being approximately 10-fold more potent than GABA.
Phaclofen ( 15.37 ) and saclofen ( 15.38 ), the phosphonic acid and sulfonic acid analogs of baclofen,
respectively, were the i rst GABA B antagonists reported. In an attempt to improve the pharmacol-
ogy and pharmacokinetics of the GABA B agonist phosphinic acid analogs mentioned above, a series
of selective and highly potent GABA B antagonists, including compound 15.39 , capable of penetrat-
ing the blood-brain barrier after systemic administration was discovered (Figure 15.9).
Predominant effects of GABA B agonists are muscle relaxation, but also various neurological and
psychiatric disorders, including neuropathic pain, anxiety, depression, absence epilepsy, and drug
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