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Chris Harvey
Medicinal Chemistry
April 26, 2007

• History
• Clinical Applications
• Mechanism of Action
• Structure
– General
– Sub-classes
– Individual examples
• Future Research

The first benzodiazepine (benzo) was synthesized by

an Austrian scientist named Dr. Leo Sternbach in the
mid 1950’s while working at Hoffman-La Roche. The
new compound’s potential as a pharmaceutical was not
initially recognized, however, Dr. Sternbach’s persistent
research eventually uncovered it’s efficacy as a
tranquilizer. In 1959, chlordiazepoxide (Librium) was
introduced as the first of many benzos to come. Just four
years later, in 1963, diazepam (Valium) came on the
market. Clinicians quickly recognized the potential of
benzos as a safer alternative to the barbiturate class of
Clinical Applications

• Anxiolytic
– GAD, PTSD, OCD, etc.
– Panic Disorder
– Specific Phobias
• Anticonvulsant
– Status epilepticus
– Myoclonic epilepsy
• Muscle relaxant
• Sleep aid
• Pre-operative anesthesia
• Alcohol withdrawal
Mechanism of Action

Benzodiazepines act
as GABA (γ-aminobutyric
acid) potentiators. They
bind to BZ receptors on
the GABA-BZ receptor
complex, which allows
them to allosterically
modulate and enhance the
activity of GABA. This
results in increased
hyperpolarization at target
neurons, making them less
responsive to excitatory
• 2-Keto Benzos
– Some administered as prodrug
– All have active metabolites Diazepam
(commonly desmethyldiazepam)
– Long half-lives (most in excess of
60 hours)
1 2
• 3-hydroxy Benzos
– No active metabolites
– Not metabolized in the liver
– Intermediate half-lives (most ~ 8-
20 hours)
• Triazolo Benzos
– Additional heterocyclic ring
attached at the 1 and 2 positions
– Some active metabolites
– Short to intermediate half-lives
(anywhere from 3-14 hours)
2-Keto Benzos

Chlordiazepoxide (Librium) Diazepam (Valium)

• First isolated benzo • Most prolific and versatile

• Oxidized to benzo
desmethyldiazepam in the liver • Indicated for treatment of
• Indicated for treatment of anxiety, seizure, muslce
anxiety and insomnia tension, insomnia, and alcohol
2-Keto Benzos

Flurazepam (Dalmane) Clonazepam (Klonopin)

• Longest half-life of any benzo • High potentcy (~ 20 times

stronger per miliigram than
(~ 40-250 hours) diazepam)
• Indicated primarily for • Causes moderate anterograde
treatment of insomnia, may amnesia
also serve as an anxiolytic
• Indicated for treatment of
anxiety, also a highly effective
2-Keto Benzos

• The original date-rape drug,

and the origin of the term
• Pharmacologically very similar
to clonazepam, but possesses
much stronger amnesic
• One of only two drugs in the
U.S. for which a first
possession charge is a
mandatory felony. The other
Flunitrazepam (Rohypnol) of the two is crack cocaine.
3-hydroxy Benzos

Lorazepam (Ativan) Oxazepam (Serax)

• Indicated for treatment of • Indicated for treatment of

anxiety, seizure, insomnia, anxiety, insomnia, and alcohol
panic disorder, and alcohol withdrawal.
withdrawal. • Common metabolite of many
• Unique among benzos in it’s 2-keto benzos following
use as an adjunctive anti- their oxidation to
emetic desmethyldiazepam
Triazolo Benzos

Alprazolam (Xanax) Triazolam (Halcion)

• First benzo approved by FDA • Very rapid onset

for treatment of panic • Very short half-life
• Possesses amnesic
• Also used as an adjunctive properties similar to
treatment for depression while clonazepam
adjusting to SSRIs.
• Used almost exclusively as
a pre-op anesthetic
Future Research
• Research is moving away from benzodiazepines
as they are being displaced by newer drugs,
which generally have fewer side-effects and lower
addiction potentials.
– Newer anxiolytics
• SSRIs (Prozac, Zoloft, Lexapro, etc.)
• Atypical anxiolytic/antidepressant drugs
– Buspirone (BuSpar)
– Venlafaxine (Effexor)
– Duloxetine (Cymbalta)
– Newer sleeping medications
• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)

• Schatzberg M.D., A. F., Cole M.D., J. O., DeBattista M.D., C. (2005)

Manual of Clinical Psychopharmacology. 5th edition. Washington
DC: American Psychiatric Publishing Inc.
• Schatzberg M.D., A. F., Nemeroff M.D., C. B. (2006) Essentials of
Clinical Psychopharmacology. 2nd edition. Washington DC:
American Psychiatric Publishing Inc.
• Katzung M.D., B. G. (2001) Basic and Clinical Pharmacology. 8th
edition. McGraw-Hill.