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History of Barbiturates The history of the discovery of the class of
drugs known as barbiturates is a classic tale, and
typical of many classes of drugs. It is filled with
romance, serendipity, taverns, chemistry, and a little
luck.
It is said
that on the Day of St. Barbara, 1864, that
artillery officers were celebrating their patron
saint in a tavern (a common practice in Europe,
even today, to celebrate one’s "saint
day").
Adolph von Baeyer
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A
German chemist, Adolph von Baeyer,
founder of what was to become the Bayer
Chemical Co., who in 1905 won the Nobel
Prize in chemistry, happened in for some
celebrating of his own. It was on that
day that he had synthesized
"malonylurea" from a reaction
of urea with malonic acid, a chemical
found in apples. No one knows exactly
what he was trying to accomplish, but
malonylurea became known as
"Barbituric acid", making St.
Barbara Day even more important! |
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19th Century Russian
Icon of St.
Barbara
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| Chemists in
the late 19th and early 20th century had few
tools to determine the properties of the chemical
compounds they made. And so they often
decided they would use one tool they had - the
reaction of their own body to the substances they
produced. Chemists tasted the stuff they
made. We don't know whether von Baeyer,
himself, tasted barbituric acid, but someone did
and found that it had no therapeutic
significance. But its discovery led to a series
of other derivatives of similar structure that
opened avenues to drugs that were significant
both therapeutically and socially. |
Barbituric Acid
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In 1903,
Fischer and von Mering were the first to
synthesize a therapeutically active
"barbiturate" by substituting two ethyl
groups for two hydrogens attached to
carbon. When they administered this
new barbiturate to human subjects, the compound
was found to induce sleep. The term for a drug
that causes sleep induction is known as a
somnolent or a hypnotic. But here is where the story gets
fuzzy! Two versions of how the compound got its
name, so you pick which you want to believe.
Version 1: von Mering was in Verona, Italy, when
he heard of the compound’s synthesis by
Fischer. Version 2 (for the romantics): Veronal,
as it became known, caused a sensation of peace
and solace that is associated with Verona.
Diethyl barbituric Acid, as Veronal was known
chemically, was a popular drug. It allowed sleep
at night, and even caused drowsiness and
relaxation when taken during the day.
Problem was, it was slow to
take effect and was very slow to wear off
due to slow metabolism. So those who took it may
wind up sleeping a day and a half!
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The chase was off.
How could the onset of action be made faster, and the
duration of action not quite as long? And of course, the
hypnotic effect would remain unchanged. This was the
goal.
| Concepts: These
early century chemists used the crudest of
tools. They measured the macroscopic result
of their chemical synthesis by giving the
chemicals to human subjects and observing the
results. Then they modified the molecular
structure by changing the compounds they used in
the reaction between malonic acid and urea.
The representations of the day were adequate in
that the overall composition of the compounds was
known - the ratio of carbon, hydrogen, oxygen and
nitrogen atoms - the stochiometry.
The sequence of what atoms were bound to what was
also known.
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Ball and stick model of
phenobarbitol.
In this model, C
is gray, H is white, O is red, N is blue.
Cylinders represent single and double
bonds. What are the advantages of this
model structure over the depiction of barbituric
acid (above)? What are the
deficiencies?
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In 1912, two
independent teams of chemists synthesized what
became known as Luminal, or phenobarbitol. In
addition to the excellent hypnotic action, the
compound was found to have anticonvulsant
activity. The compound, given twice daily, kept
seizures under control. And the hypnotic effects
could be counteracted by administering
amphetamines without affecting the anticonvulsant
properties. Subsequent
research on barbiturates began to understand that
the lack of drug activity in barbituric acid and
the slow acting effect of Veronal were caused by
the same property - negligible or slow passage
across the tissues that connect the
gastrointestinal tract to the body's circulatory
system.
The walls of the vessels
through which the drugs must pass are composed of
fatty molecules. And we learn in our
General Chemistry that if we want one substance
to dissolve in another, they two materials must
have some structural similarity - "like
dissolves like".
But barbituric acid is
insoluble in fat-like solvents and Veronal is
only slightly more soluble. The scientists
needed to develop molecules that contained larger
hydrocarbon groups that resembled the fatty
components of the body's barriers.
This idea led to
modification in the chemicals to yield very
lipophilic compounds that crossed the blood-brain
barrier quickly and those that could be
administered intravenously for pre-surgical
anesthesia. Manipulations of the side chain at
position 5 have resulted in amobarbital (Amytal
), pentobarbital (Nembutal ), and secobarbital
(Seconal ). These drugs have become widely known
as drugs of abuse. Changes in position 2 have
resulted in the short-acting barbiturates:
hexobarbital (Evipal ), thiopental (Pentothal )
and methohexital (Brevital ).
Many drugs in this class
are still widely used today. The discovery of
barbiturates and the research into the
pharmacology and chemistry of these compounds led
to the discovery of benzodiazepines. Drugs that
are widely known in this class include Valium and
Halcion . Benzodiazepines have largely replaced
barbiturates in therapy except in anesthesia.
Other anticonvulsant medications have largely
replaced phenobarbitol. Many patients, however,
still rely on its potent anticonvulsant
properties with few side effects. And in
today’s pharmaceutical marketplace,
phenobarbitol has one characteristic that makes
it unique: it is CHEAP!
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Now let's take a
look at this chemical marvel!
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