4.7.4.2 GABA Antagonists
An important direct antagonist is the alkaloid (+)-bicuculline (4.175), which binds to all
synaptic GABA sites. Being a lactone, it is sensitive to hydrolysis. Its binding is influenced by salts; that is, [
3
H] bicuculline binding in the presence of 50 µM NaSCN or
200 µM NaClO 4 is more “specific” than in the absence of salts, and only 30–50% of it
can be displaced by GABA or muscimol. This is a further indication of GABA receptor
multiplicity. Interestingly, benzylpenicillin (4.176) can antagonize GABA in doses below
2 µM, and can thus be epileptogenic. Under most circumstances this is not clinically relevant since benzylpenicillin does not cross the blood–brain barrier. However, when used
to treat diseases such as meningitis (in which the structural integrity of the blood–brain
barrier is jeopardized), benzylpenicillin can contribute to the development of seizures.
4.7.5 GABAergic Drugs: Benzodiazepines
The benzodiazepines are probably the most clinically important class of GABA-active
compounds. Benzodiazepines modify affective responses to sensory perceptions;
specifically, they render individuals less responsive to anxiety-producing stimuli and
therefore exert a strong anxiolytic action. In addition, benzodiazepines exert sedating,
anticonvulsant, and muscle relaxant effects.
The benzodiazepines were discovered by Leo Sternbach at the Hoffman–La Roche
laboratories, and their pharmacology was elucidated by Randall of the same company.
An enormous variety of these compounds exist. Since about 3500 benzodiazepine compounds have been investigated, the neurologic structure–activity relationships of these
drugs have been well established and the central features can be generalized as follows:
1. R 1 should be an electron-attracting group. Other substituents should not be attached
to any of the carbons on that ring.
2. R 2 and R 3 can be varied. Replacement of the lactam oxygen by sulfur decreases
activity.
3. The phenyl group is necessary for activity; halogen substituents are preferred in the
ortho position.
Despite these GABAergic structure–activity properties, the benzodiazepine moiety is
an extremely versatile building block or molecular platform upon which to design nonGABAergic drugs. In fact, benzodiazepines have been referred to as privileged structures. The term “privileged structure” was introduced by Evans et al. in describing the
development of benzodiazepine-like cholecystokinin antagonists based on asperlicin, a
natural product. By their definition, Evans and co-workers concluded that the benzodiazepine ring system was a privileged structure since it was “a single molecular framework able to provide ligands for diverse receptors” and that “judicious modification of
the benzodiazepine structure could be a viable alternative in the search for new receptor agonists and antagonists.” For instance, benzodiazepines are found in multiple types
of CNS agents and are ligands for both ion channels and G-protein coupled receptors.
Derivatives of benzodiazepines which are analgesics, cholecystokinin antagonists,
angiotensin II antagonists, vasopressin antagonists, and bradykinin agonists have been
described. Because of this versatility, libraries of benzodiazepines have been created to
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MEDICINAL CHEMISTRY
An important direct antagonist is the alkaloid (+)-bicuculline (4.175), which binds to all
synaptic GABA sites. Being a lactone, it is sensitive to hydrolysis. Its binding is influenced by salts; that is, [
3
H] bicuculline binding in the presence of 50 µM NaSCN or
200 µM NaClO 4 is more “specific” than in the absence of salts, and only 30–50% of it
can be displaced by GABA or muscimol. This is a further indication of GABA receptor
multiplicity. Interestingly, benzylpenicillin (4.176) can antagonize GABA in doses below
2 µM, and can thus be epileptogenic. Under most circumstances this is not clinically relevant since benzylpenicillin does not cross the blood–brain barrier. However, when used
to treat diseases such as meningitis (in which the structural integrity of the blood–brain
barrier is jeopardized), benzylpenicillin can contribute to the development of seizures.
4.7.5 GABAergic Drugs: Benzodiazepines
The benzodiazepines are probably the most clinically important class of GABA-active
compounds. Benzodiazepines modify affective responses to sensory perceptions;
specifically, they render individuals less responsive to anxiety-producing stimuli and
therefore exert a strong anxiolytic action. In addition, benzodiazepines exert sedating,
anticonvulsant, and muscle relaxant effects.
The benzodiazepines were discovered by Leo Sternbach at the Hoffman–La Roche
laboratories, and their pharmacology was elucidated by Randall of the same company.
An enormous variety of these compounds exist. Since about 3500 benzodiazepine compounds have been investigated, the neurologic structure–activity relationships of these
drugs have been well established and the central features can be generalized as follows:
1. R 1 should be an electron-attracting group. Other substituents should not be attached
to any of the carbons on that ring.
2. R 2 and R 3 can be varied. Replacement of the lactam oxygen by sulfur decreases
activity.
3. The phenyl group is necessary for activity; halogen substituents are preferred in the
ortho position.
Despite these GABAergic structure–activity properties, the benzodiazepine moiety is
an extremely versatile building block or molecular platform upon which to design nonGABAergic drugs. In fact, benzodiazepines have been referred to as privileged structures. The term “privileged structure” was introduced by Evans et al. in describing the
development of benzodiazepine-like cholecystokinin antagonists based on asperlicin, a
natural product. By their definition, Evans and co-workers concluded that the benzodiazepine ring system was a privileged structure since it was “a single molecular framework able to provide ligands for diverse receptors” and that “judicious modification of
the benzodiazepine structure could be a viable alternative in the search for new receptor agonists and antagonists.” For instance, benzodiazepines are found in multiple types
of CNS agents and are ligands for both ion channels and G-protein coupled receptors.
Derivatives of benzodiazepines which are analgesics, cholecystokinin antagonists,
angiotensin II antagonists, vasopressin antagonists, and bradykinin agonists have been
described. Because of this versatility, libraries of benzodiazepines have been created to
274
MEDICINAL CHEMISTRY