1-Oxo-5-hydroxytryptamine: A surprisingly potent agonist of the 5-HT 3 (serotonin) receptor

Article abstract of DOI:10.1021/ol071083s

A novel synthetic route to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of serotonin, has been developed. The new synthesis proceeds via the [3+2] cycloaddition of p-benzoquinone and 2,3-dihydrofuran, followed by a Lewis acid-catalyzed isomerization

Full text of DOI:10.1021/ol071083s

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3205-3207
1-Oxo-5-hydroxytryptamine: A
Surprisingly Potent Agonist of the 5-HT3
(Serotonin) Receptor
Sean M. A. Kedrowski, Kiowa S. Bower, and Dennis A. Dougherty*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
dadougherty@caltech.edu
Received May 9, 2007
ABSTRACT
A novel synthetic route to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of serotonin, has been developed. The new synthesis proceeds
via the [3 2] cycloaddition of p-benzoquinone and 2,3-dihydrofuran, followed by a Lewis acid-catalyzed isomerization. This molecule proves
+
to be a competent agonist (equipotent to serotonin) of the 5-HT3 receptor, demonstrating that the indolic proton of serotonin is not essential
to its activation of the receptor.
Following its isolation in 1948,1 5-HT (5-hydroxytryptamine,
serotonin, 1) was identified as a key signaling molecule
throughout many areas of biology. Derived from the enzy-
matic hydroxylation-decarboxylation of tryptophan, it can
be found in most multicellular organisms, although it is
primarily known as a neurotransmitter. In the mammalian
CNS (central nervous system), 1 is believed to play an
important role in many fundamental processes, such as mood,
sexuality, appetite, aggression, sleep, vomiting, and body
temperature. Abnormal levels of 1 have been correlated with
a variety of disorders, including obsessive-compulsive
disorder (OCD), clinical depression, fibromyalgia, tinnitus,
bipolar disorder, anxiety disorders, sudden infant death
syndrome, and substance abuse.2,3
The network of known macromolecular targets of 1 is
similarly broad and complexsseven families (and multiple
subfamilies) of 5-HT receptors have been identified in
humans. All but one of these receptor families are GPCRs
(G-protein coupled receptors), with the 5-HT3 class belonging
to the Cys-loop superfamily of LGICs (ligand-gated ion
channels).4,5
Cys-loop LGICs are characterized by five transmembrane
protein subunits arranged symmetrically about an ion-
conducting pore. The 5-HT3 receptor is a cation selective
channel that alters its conformation from the resting (non-
(4) For reviews of 5-HT receptors, see ref 2 and: (a) Meltzer, H. Y.; Li,
Z.; Kaneda, Y. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2003, 27,
1159-1172. (b) Barnes, N. M.; Sharp, T. Neuropharmacology 1999, 38,
1083. (c) Pucadyil, T. J.; Kalipatnapu, S.; Chattopadhyay, A. Cell Mol.
Neurobiol. 2005, 25, 553. (d) Leopoldo, A. Curr. Med. Chem. 2004, 11,
629. (e) Bishop, M. J.; Nilsson, B. M. Expert Opin. Ther. Pat. 2003, 13,
1691. (f) Poissonet, G.; Parmentier, J. G.; Boutin, J. A. Expert Opin. Ther.
Pat. 2004, 4, 325. (g) Thomas, D. R. Pharmacol. Therapeut. 2006, 111,
707.
(5) (a) Thompson, A. J.; Lummis, S. C. R. Curr. Pharm. Des. 2006, 12,
3615. (b) Reeves, D. C.; Lummis, S. C. R. Mol. Memb. Biol. 2002, 19, 11.
(c) Maricq, A. V.; Peterson, A. S.; Brake, A. J.; Myers, R. M.; Julius, D.
Science 1991, 254, 432-437. (d) Greenshaw, A. J. Trends Pharmacol. Sci.
1993, 14, 265-270. (e) Gyermek, L. J. Clin. Pharmacol. 1995, 35, 845-
855.
(1) Rapport, M. M.; Green, A. A.; Page, I. H. J. Biol. Chem. 1948, 176,
1243-1251.
(2) (a) Bloom, F. E.; Kupfer, D. J. Psychopharmacology: the fourth
generation of progress, 4th ed., official publication of the American College
of Neuropsychopharmacology; Raven Press: New York, 1995. (b) Davis,
K. L. Neuropsychopharmacology: the fifth generation of progress, official
publication of the American College of Neuropsychopharmacology;
Lippincott/Williams & Wilkins: Philadelphia, PA, 2002.
(3) Paterson, D. S.; Trachtenberg, F. L.; Thompson, E. G.; Belliveau,
R. A.; Beggs, A. H.; Darnall, R.; Chadwick, A. E.; Krous, H. F.; Kinney,
H. C. JAMA, J. Am. Med. Assoc. 2006, 296, 2124-2132.
10.1021/ol071083s CCC: $37.00
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conductive) state to the active (cation-permeable) state upon
binding to 1. As part of our efforts to better understand this
key process, we have been mapping out the binding site.6
We thus became curious as to whether the protic indole
nitrogen of 1 forms a hydrogen bond with the receptor as
part of its binding interaction.6a A valuable probe of this
putative interaction would be the benzofuran analogue of 1,
in which an aprotic oxygen replaces the indole nitrogen.
The target molecule is 3-(2-aminoethyl)benzofuran-5-ol,
which we will refer to as 1-OT (1-oxo-5-hydroxytryptamine,
2), for consistency with 5-HT and related compounds.
Structure 2 has been synthesized once before,7 but it has
never been explicitly tested on any of the known 5-HT
receptors.8,9 In considering this molecule for our own studies,
we felt that the published synthesis (10 steps and <3% yield)
was cumbersome, and we chose to pursue a novel synthetic
strategy that could provide more ready access to 2. Identi-
fication of the quinone synthon within the target molecule
suggested a synthetic route utilizing a [3+2] cycloaddition
between p-benzoquinone and an electron-rich olefin,10,11
yielding the properly substituted benzofuran core in a single
step (Scheme 1).
Scheme 2. Synthesis of 1-Oxo-5-hydroxytryptamine
a Reference 11.
cycle 6 is a known compound that can be prepared enantio-
selectively by the formal [2+3] cycloaddition of 3 with 2,3-
dihydrofuran (7) by using an oxazaborolidine catalyst
developed by Corey.11 We discovered that the same trans-
formation can be accomplished racemically by BF3‚Et2O,
albeit in much poorer yield. Treatment of the cycloaddition
product 6 with concentrated HCl or HBr failed to give 8 or
the corresponding primary halide. However, BF3‚Et2O was
able to accomplish this transformation in good yield at
slightly elevated temperatures. Neither BF3‚Et2O nor a variety
of other Lewis acids (MgBr2, AlCl3, InCl3, ZnBr2) proved
capable of executing the cycloaddition-isomerization se-
quence in a single pot.13
Scheme 1. Retrosynthetic Analysis of
1-oxo-5-hydroxytryptamine
To realize this strategy, we first attempted the cyclo-
addition of p-benzoquinone (3) with enamine 4, which, when
subjected to acidic workup conditions, was expected to give
ring-opened product 2. However, consistent with previous
reports,12 we found pyrroline (4) very difficult to work with
due to its high reactivity (4 readily forms trimers at room
temperature), and we were never able to isolate the desired
product from the reaction mixture. We then considered
protection of 4 with an electron-withdrawing carbamate or
amide to reduce its reactivity; however, the N-benzoyl
compound 5 failed to react with 3.
Installation of the primary amine by using Fukuyama’s
modified Mitsunobu protocol14 worked well, giving the
protected amine 10 in quantitative yield. Double deprotection
of 10 with basic thioglycolic acid, followed by HCl in
We then considered installing the amine subsequent to the
formation of the heterocyclic framework (Scheme 2). Tri-
(6) (a) Beene, D. L.; Price, K. L.; Lester, H. A.; Dougherty, D. A.;
Lummis, S. C. R. J. Neurosci. 2004, 24, 9097-9104. (b) Bower, K. S.;
Price, K. L.; Sturdee, L. F.; Dougherty, D. A.; Lummis, S. Submitted for
publication.
(7) Hallmann, G.; Hagele, K. Leibigs. Ann. Chem. 1963, 662, 147.
(8) There is one published pharmacological experiment on 1-OT (ref
9): the drug was assayed by measuring the rate of muscular contraction
following drug application to surgically removed rat fundus strips.
(9) Pinder, R. M.; Green, D. M.; Thompson, P. B. J. Med. Chem. 1971,
14, 626-628.
(10) (a) Domschke, G. J. Prankt. Chem. 1966, 32, 144. (b) Yadav, J. S.;
Reddy, B. V. S.; Kondaji, G. Synthesis 2003, 1100-1104.
(11) Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 11958-11959.
(12) (a) Nomura, Y.; Ogawa, K.; Takeuchi, Y.; Tomoda, S. Chem. Lett.
1977, 693-696. (b) Kraus, G. A.; Neuenschwander, K. J. Org. Chem. 1981,
46, 4791-4792. (c) Marais, W.; Holzapfel, C. W. Synth. Commun. 1998,
28, 3681-3691.
Figure 1. Dose-response curves for 5-HT and 1-OT with sample
current traces inset.
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Org. Lett., Vol. 9, No. 17, 2007

chloroform-methanol gave 2, which could be crystallized
from anhydrous ether as its hydrochloride salt in 65% yield
from 10.
(5-fluorotryptamine, 11), is a partial agonist with an efficacy
of only 30% that of 1 and an EC50 that is 10-fold shifted
(16 ( 1.8 µM).6b
The pharmacology of 2 on the 5-HT3 receptor proved very
interesting, as its EC50 (effective concentration for half-
maximal response) value is nearly identical with that of the
native agonist, 1 (1.7 ( 0.06 vs 1.2 ( 0.03 µM, respectively;
Figures 1 and 2). Furthermore, 2 is essentially a full agonist,
In conclusion, we have established an efficient new route
to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of
serotonin. We have further shown that this molecule is a
competent agonist of the 5-HT3 receptor, suggesting that the
indole nitrogen of 1 does not donate a hydrogen bond to the
receptor. The increased availability of 2 afforded by the
synthetic route described here will enable similar studies to
elucidate agonist binding in the other six classes of 5-HT
receptors. In addition, this route should be easily modifiable
(through the use of substituted benzoquinones and dihydro-
furans) to synthesize more substituted 1-OT derivatives for
further elucidation of 5-HT receptor binding sites.
Acknowledgment. This work was supported by the NIH
(NS 34407) and an NIH training grant for S.K. (NRSA
5-T32-GM07616).
Supporting Information Available: Full experimental
1
procedures, characterization data, and copies of H and 13C
NMR for all synthesized compounds, procedures for the
experiments on the 5-HT3 receptor, and dose-response
curves for 1 and 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 2. Pharmacology of 5-HT, 1-OT, and 5-FT on the 5-HT3
receptor.
OL071083S
(13) It is further worth noting that when pure 6 was subjected to the
isomerization conditions in the presence of quinone 3, no product 8 could
be observed.
with an efficacy that is (94 ( 4)% of 1. Surprisingly, the
indole NH of 1 is not required for effective receptor
activation. In sharp contrast, another subtle variant of 1, 5-FT
(14) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353-359.
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