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r’KoeJ. BPharrrtacol.
K & Weissman .1.t p-Chlorophenvlalanine: a specific depletor of brain seroronin.
Exp. Tr rer. 154:499-516, 1966.
[Pfizer Inc.. Groton, CTI
p-Chlorophenylalanine PCPA) was reported in this PCPA was not our only basic discovery during the
mid-i 960s. In 1965, after cx-methyltyrosine (AMT)
paper to markedly deplete brain and peripheral stores
of serotonin and 5-hydroxyindoleacetic acid in aniand its m-iodo derivative were reported to inhibit
mals. Catecholamine concentrations were reported to
tyrosine hydroxylase,3 we learned that Pfizer diembe only slightly affected. Mechanistic studies indiists had coincidentally synthesized a one-step precated that PCPA effects serotonin depletion by inhibitcursor to AMT for a different purpose, enabling our
ing the biosynthesis ofthe monoamine at the tryptorapid conduct of in vivo experiments. In planning
phan hydrosylase step. [The sci’~
indicates that this
one of these, we predicted that AMT would increase
paper has been cited in over 1,605 publications4
a rat’s sensitivity to amphetamine by what was then
termed denervation supersensitivity. The behavioral
experiments yielded exactly opposite effects to
—~ S ~
those expected, and we were the first to report that
PCPA: An Example of Serendipity
AMT blocks amphetamine-elicited stimulation,s,S a
finding that teaches much about how amphetamine
A. Weissman and B.l(. Koe
exerts its stimulant action,
Central Research
These forays into the pharmacology of ring-haloPfizer Inc.
genated aromatic amino acids also led us to a neGroton, CT 06340
glected literature that low doses of mJune 11, 1990
fluorophenylalanine (m-FP) and m-fluorotyrosine
The year 1991 will mark the twenty-fifth anniver- (rn-Fr) are convulsant and lethal in rodents. While
wondering
how this toxicity could result from
sary of our often-cited report that p-chlorophenylchanges in brain amines, one of us, just then beginalanine (PCPA) depletes serotonin in mice, rats, and
ning a banal self-education project, found himself
dogs by inhibiting tryptophan hydroxylase. Here is
reading areview of fluoroacetate toxicity in volume
how the discovery was made: when p’-chloroam1 of Phannacologic.al Reviews.’ Could lethal synphetamine was reported to moderately decrease
thesis
to fluoroacetate be the mechanism of m-FP
serotonin concentrations in rat brain (e.g., refer.
and
rn-Fr toxicity? Yes, and also of 5-Iluorotryp1), we quickly confirmed the finding and tried
tophan toxicity, and analyzing7~the metabolic pathto extend it by testing likely metabolic precursors to
p-chlorophenethylamines, among them PCPA. For- ways had surprising beneflts.
Our main reason for reviewing these events is to
tuitously, serotonin concentrations were examined
emphasize that they were not predided or sought in
in rats at both 1 and 24 hours after treatment. Later
advance.
We can provide many other anecdotes
we found that marked serotonin depletion in rat
describing fortuitous drug discoveries. We are conbrain after PCPA could only have been detected
cerned that similarly important serendipitous disafter approximately 24 hours and that had we used
coveries seem to be less often made these days. For
mice the effect would have been less remarkable. In
understandable reasons, the pharmaceutical indusprobing for the mechanism of the in vivo effect, we
try now attempts to rationalize discovery refound that PCPA much more effectively than p-chlosearch— to focus limited resources on proprietary
roamphetamine blocks the hydroxylation of trypto—
goals, to foster teamwork, to minimize animal use,
phan and phenylalanine.
Since our disclosure, PCPA has served as a re- and to satisfy a widespread belief that modern drugs
search tool for inhibiting serotonin biosynthesis ant.,
should be discovered and analyzed by using deductive logic. Analogous beliefs underlie the phifor other purposes. The scope of experiments conlosophies of most public and academic institutions
ducted with PCPA, usually based on information
and samples provided by our company, and the
that support research. But relying upon deductive
reasoning as the sole basis for ftinding research, in
scientific impact of PCPA have been extraordinary.
PCPA perfectly illustrates the vast, mostly unsun
our judgment, can undermine the possibility of just
contributions industrial pharmacological
researc
such serendipity as that we were lucky enough to
2
has made to basic science.
encounter a quarter-century ago.
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2.
3.
4.
5.
6.
7.
5.
9.
Ptetcher A. Burkard W P. Brudnrer H & Gey K F. Decrease of cerebral 5-hydrosvrrcpramine md
5-ltydroxyindoleacetic acid by an arylalkylamine. Life Sci. 2:828-33. 1963. (Cited 45 times.)
Weissman A & Koe B K. Contributions of industrial research to basic uearspsychopltarmacolagy: gre-clinical screening
and discovery. )Meltzer H I. ed.) Pssrhvphor,nacologv, the third genera/ion of progress. New York: Raven Press,
1987. p. 649-37.
Udenfriend S. Zaitzmsn-Nirenberg P & Nagatsu T. Inhibitors of purified beef adrenal yrosine hydrovylase.
Biochent, Fharntacol. 4:837-45. 1965. (Cited 315 times.)
Wejssman .4 & Kne B K, Behavioral effects of L.alpha-methyl~tyt-osine.an inhibitor of tyrosioe hydroxylase.
Life Sci. 4:1037-48. 1965. (Cited 140 times,)
Weissman A. Koe B K & Texan S S. Antianrphetamine effects following inhibition of tyrosine hydroxylase.
J. Pharntucol, trcp. Thee, 31:339-52. 1966. (Cited 463 times.l
Chenoweth M B. Monotluoroacetic acid and related compounds. Phur-rrai’vl. Ret’. l:383-44. 1949. (Cited 85 times.(
Kne B K & Weissman A. Convulsions and elevation of tissue citric acid levels ioducrd by 5.tluorotryptophan.
Bic,c hem. Pharmacol. 15:2134-6. 966. (Cited 5 times.)
Weissman A & Koe B K. m-Fluorstyrostne convulsions and mortality: relationship in catecholamine and citrate
metabolism. J. Pharrnacol. Erg. Thee. 155:135-44. 1967. (Cited 15 times.)
Koe B K & Wejssman A, Dependence of m-fluorophenvlalanine toxicity on phenylalaoirte hydrosylase activity.
I. Pharmai’o(. E.rp. Thee. 157:565-73. 1967. (Cited It limes.)
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LS, V.33. 4141. Oct. 8, 19~O
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