Medicinal Chemistry

doses; at high doses, it also inhibits succinic semialdehyde dehydrogenase, the enzyme
oxidizing the semialdehyde. As this metabolite accumulates, GABA-T activity is
decreased by end-product inhibition, and the neurotransmitter concentration increases,
thus inhibiting seizures. Ethosuximide, like valproate, blocks the T-type Ca^2 +channel.
Vigabatrin is a GABA transaminase inhibitor that causes dramatic increases in brain
GABA levels. It produces side effects in the form of psychosis and visual field con-
striction (due to retinal damage); both of these side effects may be GABA-mediated.
Finally, as stated above, clobazam is a GABAAagonist.
γ-Aminobutyric acid also seems to be involved in a number of other physiological
and pathological functions, including feeding, sleep, hormonal secretion, cardiovascu-
lar functions, and, most importantly, general anesthesia.

4.7.8 GABAergic Drugs: General Anesthetics

Richard Feynman, the Nobel-prize winning physicist, once wrote:

I wonder why. I wonder why.

I wonder why I wonder.

I wonder whyI wonder why

I wonder why I wonder!

This simple quatrain wonderfully epitomizes the essence of the human mind.
Awareness of one’s inner and outer environments is central to the functioning of the
human mind. Consciousness is the enigmatic phenomenon that is crucial to the inter-
face between brain and mind. General anesthetics are drugs that temporarily rob us of
our consciousness; GABA is a key molecular target for general anesthesia.
Many general anesthetic agents work at the level of the GABAAreceptor. This
GABAergic mechanism for general anesthesia accounts for the observation that many
benzodiazepines (midazolam,4.184), barbiturates (thiopental,4.190), and other anti-
convulsants are both anticonvulsants and general anesthetics. In addition, a number of
general anesthetics, such as propofol (4.201) and etomidate (4.202), bind to the GABAA
receptor. This recent implication of GABA receptors in general anesthesia provides
intriguing evidence for the role of GABAergic mechanisms in a molecular-level under-
standing of human consciousness—that most enigmatic of physiological processes.
Indeed, the riddle of human consciousness has been described by Francis Crick, the
Nobel-prize-winning biologist, as the major unsolved problem in biology.

280 MEDICINAL CHEMISTRY