5-Thienyltryptamine derivatives as serotonin 5-HT(1B/1D) receptor agonists: Potential treatments for migraine

Article abstract of DOI:10.1016/S0960-894X(00)00133-5

A series of 5-(2- or 3-thienyl)tryptamine derivatives (9) has been synthesized and shown to be potent and selective 5-HT(1D) versus 5-HT(1B) receptor agonists and, therefore, potential treatments for migraine. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00133-5

Bioorganic & Medicinal Chemistry Letters 10 (2000) 903±905
5-Thienyltryptamine Derivatives as Serotonin 5-HT1B/1D Receptor
Agonists: Potential Treatments for Migraine
Charles Q. Meng,*,y Suman Rakhit,{ David K. H. Lee,x Rajender Kamboj,
Kirk L. McCallum, Lucy Mazzocco, Kerry Dynex and Abdelmalik Slassi*
NPS Allelix Corp., 6850 Goreway Drive, Mississauga, Ontario, Canada, L4V 1V7
Received 5 October 1999; accepted 15 February 2000
AbstractÐA series of 5-(2- or 3-thienyl)tryptamine derivatives (9) has been synthesized and shown to be potent and selective 5-HT1D
versus 5-HT1B receptor agonists and, therefore, potential treatments for migraine. # 2000 Elsevier Science Ltd. All rights reserved.
Migraine is a common, highly distressing disorder
a€ecting normal daily life and economic productivity.1
The introduction of sumatriptan (1)2 (Fig. 1) into clin-
ical practice has revolutionized migraine drug discovery
and spurred further research for better treatments.3
Several related compounds such as zolmitriptan (2) and
naratriptan (3) have recently emerged on the market.
These drugs are all serotonin receptor agonists and are
collectively known as `triptans'. The triptan class of
antimigraine drugs bind to the 5-HT1D (5-HT1Da pre-
viously), 5-HT1B (5-TH1Db previously) and 5-HT1F
receptors with high anities.3 Although the exact
pathophysiology of migraine is unclear: direct vasocon-
strictor e€ect on the cranial blood vessels4 and/or inhi-
bition of neurogenic in¯ammation in the dura mater,5 it
is generally accepted that one or more of the three
receptors to which the triptans bind is involved in
migraine. While all three receptors (5-HT1D, 5-HT1B
and 5-HT1F) have been found in human trigeminal
ganglia, only 5-HT1B and 5-HT1F receptors are clearly
present in cerebral blood vessels.6 The vasoconstrictor
e€ect could be mediated by the 5-HT1B or 5-HT1F
receptors while the neurogenic e€ect by any of the three.
symptoms.7 However, sumatriptan has shown no e€ect
in the neurogenic model of knockout mice lacking the 5-
HT1B receptor.8 In addition, the 5-HT1F receptor is also
a potential target for migraine. LY-334370 is a 5-HT1F
receptor speci®c ligand.9 It has shown satisfactory phase
II results, but was abandoned for safety reasons.
It has been shown that adverse cardiovascular e€ects
associated with sumatriptian can be attributed to its
5-HT1B receptor10 which is present in human coronary
arteries.11 Other members of the triptan class also bind
to the 5-HT1B receptor and will likely cause the same
cardiovascular side e€ects as sumatriptan. Thus, the
search for the next generation of antimigraine drugs has
focussed on achieving 5-HT1D/5-HT1B selectivity. To
this end over 300-fold selectivity has been achieved in
the indole series12 and over 6000-fold selectivity in a
non-indole series.13 Since it is not certain whether the 5-
HT1D receptor alone is involved in the pathogenesis
and/or treatment of migraine, it will be very interesting
and important to see if these highly selective compounds
show ecacy in humans.
In this Letter, we report the synthesis and biological
evaluation of a series of 5-thienyltryptamine derivatives
(9) as potential treatments for migraine. These com-
pounds were synthesized by a cross-coupling reaction
between the thiophene and the indole segments. As shown
in Scheme 1, commercially available 5-bromoindole 4
was acylated by treatment with oxalyl chloride in diethyl-
ether at 0 ꢀC and then re¯uxed overnight to a€ord inter-
mediate 5. It was further reacted with an excess amount
of a variety of amines to give compounds 6, which were
coupled with thiopheneboronic acids under the Suzuki
conditions14 to give the targeted 5-thienyltryptamine
It has been proposed that selective agonists of the 5-HT1D
site alone might be e€ective in ameliorating migraine
*Corresponding authors. Tel.:+1-678-336-2540; fax: +1-678-336-
2501; e-mail: cmeng@atherogenics.com (C.Q.M.); Tel.: +1-905-677-
0831; fax: +1-905-677-9595; e-mail: slassi@allehx.com (A.S.)
yCurrent address: AtheroGenics Inc., 8995 Westside Parkway,
Alpharetta, GA, 30004, USA.
{Current address: MCR Research Inc., 4700 Keele St. Toronto ON
Canada M3J 1P3.
xCurrent address: Maxxam BioDiscoveries Inc., 101 Resources Rd,
Toronto, ON, Canada, M9P 3T1.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00133-5

904
C. Q. Meng et al. / Bioorg. Med. Chem. Lett. 10 (2000) 903±905
derivatives 9. Alternatively, bromides 6 were converted
to their tin derivatives 8 by reaction with dibutylditin
and catalytic Pd(0) in toluene at re¯ux, and then cross-
coupled with a bromothiophene under the Stille condi-
tions.15 This manipulation is useful when the corre-
sponding thiophenboronic acid is not commercially
available. The reduction of the dicarbonyl intermediate
with four equivalents of lithium aluminum hydride in
re¯uxing tetrahydrofuran gave 5-thienyltryptamine
derivatives 9 as ®nal product suitable for biological
evaluation.
A synthesis starting from serotonin was also pursued.
As shown in Scheme 2, the primary amine of serotonin
Figure 1.
Scheme 1. Reagents and conditions: (a) oxalylchloride, diethylether, 0 ꢀC, then re¯ux overnight; (b) amines, triethylamine in tetrahydrofuran, RT/2
h; (c) Bu3SnSnBu3, PdPh3P4, toluene, re¯ux overnight; (d) thiopheneboronic acid, PdPh3P4, Na2CO3, DME, re¯ux/4 h; (e) thiophenebromide,
PdPh3P4, Na2CO3, DMF, re¯ux/overnight; LAH, tetrahydrofuran, re¯ux/4 h.
Scheme 2. Reagent and conditions: (a) 2-thiopheneboronic acid, PdPh3P4, Na2CO3, DME, re¯ux/4 h; (b) NH2NH2, RT/overnight.

C. Q. Meng et al. / Bioorg. Med. Chem. Lett. 10 (2000) 903±905
905
5-HT1B receptors were gained, but the 5-HT1D/5-HT1B
selectivity decreased (compare 9k with 9f).
Table 1. Binding pro®le of 5-Thienyltryptamine derivatives 9 in
comparison with sumatriptan at the cloned human 5-HT1D and 5-
HT1B receptors
In summary, we have discovered a series of 5-thieny1-
tryptamine derivatives as potent, selective 5-HT1D/1B
Compound 5-HT1D, Ki, (nM)a 5-HT1B (Ki, nM)a 5-HT1B/5-HT1D
receptor agonists. Some of them are 10 times more
potent at the 5-HT1D receptor and 10 times more 5-
HT1D/5-HT1B selective than sumatriptan. These com-
pounds are currently under pharmacological evaluation
which will be reported separately.
Sumatriptan
11
1.7
0.7
0.5
3.2
7.6
19
31
2.5
8.2
1.8
4.5
36
32
23
17
133
303
714
476
70
113
9.9
107
3.2
18.8
32.8
34
41.5
39.8
37.5
15.3
28
9a
9b
9c
9d
9e
9f
9g
9h
9i
13.7
5.5
23.7
References and Notes
9j
9k
1. Migraine: Pharmacology and Genetics; Sandler, M.; Ferrari,
M.; Harnett, S., Eds.; Altman: London, 1996.
2. Plosker, M.; McTavish, D. Drugs 1994, 47, 622.
3. Meng, C. Q. Curr. Med. Chem. 1997, 4, 385.
4. Humphrey, P. P. A.; Goaadsby, P. J. Cephalalgia 1994, 14,
401.
5. Buzzi, M. G.; Bonamini, M.; Moskowitz, M. A. Cephalalgia
1995, 15, 277.
6. Bouchelet, I.; Cohen, Z.; Casee, B.; Seguela, P.; Hamel, E.
Mol. Pharmacol. 1996, 50, 219.
7. (a) Rebeck, G. W.; Maynard, K. I.; Hyman, B. T.;
Moskowitz, M. A. Proc. Natl. Acad. Sci. USA 1994, 91, 3666;
(b) Moskowitz, M. A.; Macfarlane, R. Brain Metab. Rev.
1993, 5, 159.
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Macor, J. E.; Chaveau, J.; Moskowitz, M. A. Mol. Pharmacol.
1996, 49, 761.
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aKi values are given as the mean of at least two independent determi-
nations performed in duplicate.
was ®rst protected as a phthalimide and the phenol
group was converted to the tri¯ate to give intermediate
10.16 Cross-coupling with 2-thiopheneboronic acid
under Suzuki conditions a€orded compound 11.
Finally, cleavage of phthalimide with hydrazine gave 5-
thienyltryptamine 9a.
As shown in Table 1, all compounds reported here
exhibited high anity for the 5-HT1D receptor; most of
them being more potent than or comparable to suma-
triptan. In all cases, better 5-HT1D/5-HT1B selectivities
were observed when compared to sumatriptan, some
being over 10 times better. Both 2- and 3-thienyl analo-
gues displayed very similar binding pro®les at both 5-
HT1B receptors (compare 9b with 9c). Introduction of a
substitution to the 5-position of the thieny1 ring in the
N,N-dimethylamine series results in an at least 5-fold
lower anity for both the 5-HT1D and 5-HT1B receptors
(compare 9b and 9d with 9e), and slightly increased 5-
HT1D/5-HT1B selectivity. The same trends are not
observed in the pyrrolidine analogues (compare 9f with
9g). N,N-Dimethylamine derivative 9b, showed an
increased 5-HT1D/5-HT1B selectivity over the corre-
sponding primary amine 9a. The pyrrolidine derivative
9f binds with almost 30-fold lower anity than the N,N
dimethylamine analogue 9b at both 5-HT1D and 5-HT1B
receptors. Introduction of mono- or di-substitutions to the
pyrrolidine ring results in higher anity, though not to
the same extent at 5-HT1D and 5-HT1B receptors. In fact,
12. Castro, J. L.; Collins, I.; Russell, M. G. N.; Watt, A. P.;
Sohal, B.; Rathbone, D.; Beer, M. S.; Stanton, J. A. J. Med.
Chem. 1998, 41, 2667.
13. Ennis, M. E.; Ghazal, R. L.; Smith, M. W.; Schlachter, S.
K.; Lawson, C. F.; Im, W. B.; Pregenzer, J. F.; Svensson, K.
A.; Lewis, R. A.; Hall, E. D.; Sutter, D. M.; Harris, L. T.;
McCall, R. B. J. Med. Chem. 1998, 41, 2180.
14. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513.
the methoxymethyl derivative (9j) has the lowest 5-HT1D
5-HT1B selectivity. When a double bond is introduced
into the pyrrolidine ring, potencies at both 5-HT1D and
/
15. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
16. Barf, T. A.; de Boer, P.; Wikstrom, H. J. Med. Chem.
1996, 39, 4717.