Section 30.4 Random Screening 1211Paul Ehrlich (1854–1915)was a
German bacteriologist. He received a
medical degree from the University of
Leipzig and was a professor at the
University of Berlin. In 1892, he
developed an effective diphtheria
antitoxin. For his work on immunity,
he received the 1908 Nobel Prize in
physiology or medicine, together with
Ilya Ilich Mechnikov.symptoms for 72 hours (Section 5.13). When (isomethadone) was
introduced, it was initially thought to be the long-sought-after nonaddicting painkiller.
However, it was later found to have no therapeutic advantage over less toxic and more
effective analgesics.Notice that morphine and all the compounds prepared by molecular modification of
morphine have a structural feature in common—an aromatic ring attached to a quater-
nary carbon that is attached to a tertiary amine two carbons away.30.4 Random Screening
The lead compound for the development of most drugs is found by screening
thousands of compounds randomly. A random screen, also known as a blind screen,
is a search for a pharmacologically active compound without having any information
about which chemical structures might show activity. The first blind screen was car-
ried out by Paul Ehrlich, who was searching for a “magic bullet” against try-
panosomes—the microorganisms that cause African sleeping sickness. After testing
more than 900 compounds against trypanosomes, Ehrlich tested some of his com-
pounds against other bacteria. Compound 606 (salvarsan) was found to be dramatical-
ly effective against the microorganisms (spirochetes) that cause syphilis.
An important part of random screening is recognizing an effective compound. This
requires the development of an assay for the desired biological activity. Some assays
can be done in vitro (in glass)—for example, searching for a compound that will inhibit
a particular enzyme. Others are done in vivo—for instance, searching for a compound
that will save a mouse from a lethal dose of a virus. One problem with in vivo assays is
that drugs can be metabolized differently by different animals. Thus, an effective drug
in a mouse may be less effective or even useless in a human. Another problem involves
regulating the dosages of both the virus and the drug. If the dosage of the virus is too
high, it might kill the mouse in spite of the presence of a biologically active compound
that could save the animal. If the dosage of the potential drug is too high, the drug might
kill the mouse whereas a lower dosage would have saved it.
The observation that azo dyes effectively dyed wool fibers (animal protein) gave
scientists the idea that such dyes might selectively bind to bacterial proteins, too. WellCC CC CCCNDarvon®NCHCH 2CCCH 3CH 3CH 3O CH 2 CH 3
methadoneNCHCH 2CCOCH 3CH 3CH 3CH 3 CO CH 2 CH 3α-acetylmethadolNCHCH 2CCCH 3CH 3CH 3O CH 2 CH 3
isomethadone
DarvonIlya Ilich Mechnikov (1845–1916),
later known as Elié Metchnikoff, was
born in the Ukraine. He was the first
scientist to recognize that white blood
cells were important in resistance to
infection. Metchnikoff succeeded
Pasteur as director of the Pasteur
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