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August 2002
Volume 66 |
Number 8
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WHAT'S NEW IN …
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| … Drug
Discovery: You Saw It Here First! |
Jeffrey H. Silverstein,
M.D.
New anesthetic drugs appear from time to time. We learn about
them from reading the early laboratory work, following the clinical
trials, reading the ads or eating with the detail persons. What
we do not hear a lot about is how the compounds were initially
discovered and synthesized, a job left to the chemists. A recent
article did catch our attention not only for the ingenuity of
the process but also the implications the process may have for
pharmaceutical development.
In a recent issue of Angewandte Chemie (2002; 114/6), Nobel Laureate
K. Barry Sharpless and his colleagues describe the formation of
a powerful acetylcholinesterase (AChE) inhibitor by means of a
drug discovery strategy called "click chemistry" –
a method in which the target molecule, in this case AChE itself,
catalyzes the reaction that forms the inhibitor.
The strategy is simple and elegant. The reaction depends on binding
to two ligands to adjacent sites on the target. At the base of
a small gorge lined with aromatic side chains, AChE contains the
binding sites of its active center. There also is a peripheral
receptor at the rim of the gorge. The strongest inhibitors are
large enough to bind both sites simultaneously. Ligands to these
two receptor sites are "decorated" with reactive groups.
When the ligands bind, those reactive groups that are in proper
proximity form bonds, creating a potentially strong antagonist
that binds both sites simultaneously. By choosing reactive groups
whose reaction depends upon enforced propinquity and proper alignment
(i.e., they really have to line up perfectly in order for them
to form a bond), the random formation of dud compounds is avoided.
The investigators prepared "a selection of site-specific
inhibitors based on tacrine and phenanthridinium motifs decorated
with alkyl azides and alkyl acetylenes of varying chain lengths."
Ninety-eight potential different bivalent inhibitors could be
synthesized. Each of the potential mixtures was mixed with AChE.
In the absence of AChE, no reactions occurred. Therefore, any
reaction products that occur in the presence of the enzyme represent
a potential hit. Ultimately, only one pair was produced in a detectable
amount. On subsequent testing, that compound was found to be the
most potent noncovalent AChE inhibitor by two orders of magnitude.
The implications for drug discovery are intriguing. Prior to
this, one might have to synthesize all 98 compounds and test each
one individually. The fact that this method rapidly forms an inhibitor
so much more potent than anything previously synthesized adds
to the excitement. Could we design more potent anesthetic agents
with this process? Perhaps more fanciful, could this type of reaction
be carried out in vivo, such that we injected a group of building
block molecules that assemble into the active drug only in the
presence of the receptor? Whatever the polymorphism, if the most
potent drugs self-formed at the effector site, this could be a
highly effective drug delivery mechanism with the potential to
greatly minimize side effects from circulating drugs.
A little technical? Perhaps. In a few years, remember that you
read about it here in the ASA NEWSLETTER first!
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Jeffrey
H. Silverstein, M.D., is Associate Dean for Research, Vice-Chair
for the Institutional Review Board, Vice-Chair for Research
and Assistant Professor of Anesthesiology, Surgery, Geriatrics
and Adult Development at Mt. Sinai School of Medicine, New
York, New York. |
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