5-Alkyltryptamine derivatives as highly selective and potent 5-HT(1D) receptor agonists

Article abstract of DOI:10.1016/S0960-894X(00)00322-X

A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure-activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied.

Full text of DOI:10.1016/S0960-894X(00)00322-X

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1707±1709
5-Alkyltryptamine Derivatives as Highly Selective and Potent
5-HT1D Receptor Agonists
Abdelmalik Slassi,a,* Louise Edwards,a Anne O'Brien,a Charles Q. Meng,y
Tao Xin,a Caroline Seto,a David K. H. Lee,{ Neil MacLean,a Donna Hynd,
a Cora Chen,a Hong Wang,a Rajender Kamboja and Suman Rakhitx
aNPS Allelix Corp., 6850 Goreway Drive, Mississauga, Ontario, Canada L4V 1V7
Received 14 November 1999; accepted 30 May 2000
AbstractÐA series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized.
The structure±activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied.
Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-
HT1B/5-HT1D 125-fold) that have potential for treating acute migraine. # 2000 Elsevier Science Ltd. All rights reserved.
Migraine is a common, highly distressing disorder
a€ecting normal daily life and economic productivity.1
Approximately 8.7 million women and 2.6 million men in
the United States su€er from migraine headaches.2 The
introduction of sumatriptan2 (1) into clinical practice has
revolutionized migraine drug discovery and spurred fur-
ther research for better treatments.3 While sumatriptan is
e€ective as a migraine abortive agent, about 15% of
patients fail to respond to treatment and up to 40% may
su€er from recurrence of headache within 24 h.4,5 Similar
rates of headache recurrence have also been observed
with other antimigraine treatments such as naratriptan
(2) and eletriptan (3) (Fig. 1). These antimigraine drugs,
collectively known as ``triptans'', bind to the 5-HT1D (5-
HT1Da previously), 5-HT1B (5-HT1Db previously) and 5-
HT1F receptors with high anities.3
the pain is generated.3,6,7 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.8 The vasoconstrictor
e€ect could be mediated by the 5-HT1B or 5-HT1F
receptors while the neurogenic e€ect could be mediated
by any of the three. It has been proposed that selective
agonists of the 5-HT1D site might be e€ective in amelior-
ating migraine symptoms.7,9 The same lines of argument
have been used for the development of 5-HT1F receptor
selective agonists since the 5-HT1F receptor appears to be
present on trigeminal nerve terminals but is not vaso-
constrictive on blood vessels.10 An advanced compound
in this class was LY334370 that was known to be potent in
the dural extravasation assay11 and had shown satisfactory
phase II results, but was abandoned for safety reasons. In
addition, it has been shown that adverse cardiovascular
e€ects associated with sumatriptian can be attributed to
its 5-HT1B receptor binding.11 Other members of the trip-
tan class also bind to the 5-HT1B receptor and will likely
cause the same cardiovascular side e€ects. Thus, the
search for the next generation of antimigraine drugs has
focused on achieving 5-HT1B/5-HT1D selectivity. To this
end, selectivity over 300-fold has been achieved in the
indole series12 and over 6000-fold in a nonindole series.13
Since it is not certain that the 5-HT1D receptor alone is
involved in the pathogenesis and/or treatment of migraine,
it will be very interesting to see if highly selective com-
pounds show ecacy in humans.
Although the exact pathophysiology of migraine is not
completely understood, it appears that the pain of migraine
may in part derive from stimulation of the trigeminal sen-
sory system, which innervates meningeal and cerebral
arteries.3,6 Cranial vasodilation or neural stimulation or
both have been suggested as possible mechanisms by which
*Corresponding author. Tel.: +1-905-677-0831; fax: +1-905-677-9595;
e-mail: slassi@allelix.com
yCurrent address: AtheroGenics Inc., 8995 Westside Parkway,
Alpharetta, GA 30004, USA
{Current address: Maxxam BioDiscoveries Inc., 101 Resources Road,
Toronto, Ontario, Canada M9P 3T1
xCurrent address: MCR Research Inc., 4700 Keele St. Toronto,
Ontario, Canada M3J 1P3
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00322-X

1708
A. Slassi et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1707±1709
Figure 1.
Scheme 1. Reagent and conditions: (i) oxalyl chloride, diethyl ether, 0 ꢀC, then re¯ux overnight; (ii) R1R2NH, Et3N, THF, rt, 2 h; (iii) LAH, THF,
re¯ux, 4 h; (iv) (a) EtMgBr, THF, 0 ꢀC, 30 min; (b) Cbz-proline-acid chloride, THF, 0 ꢀC, 1.5 h.
As a continuation of our e€orts to develop highly potent
selective 5-HT1D ligands for the treatment of migraine,14
this communication describes the synthesis and biologi-
cal evaluation of a series of 5-alkyltryptamines (6) and
conformationally constrained 5-alkyl-3-(N-methylpyr-
rolidin-2-yl-methyl) analogues (8) (Scheme 1).
Table 1. Binding pro®le of 5-alkyltryptamine derivatives 6 and 8 in
comparison with sumatriptan at the cloned human 5-HT1D and 5-
HT1B receptors, and rabbit saphenous vein (RSV) functional data
Compounda
5-HT1D
(Ki, nM)a
5-HT1B
(Ki, nM)a
5-HT1B
5-HT1D
/
RSV
(EC50, nM)b
Sumatriptan
5.5
16
45
0.4
5.3
2.5
3.5
0.97
0.29
0.25
47.9
286
1625
14.2
472
312
118
47
8.7
17.8
36
34.6
89
125
33.7
49
36
62
173.5
350
6a
6b
6c
6d
6e
8a
8b
8c
8d
Acylation of 5-alkylindole (4) by treatment with oxalyl
chloride in diethyl ether at 0 ꢀC and re¯uxing overnight
a€orded the corresponding acid chloride as intermediate,15
which was further reacted with an excess amount of
N,N-dimethylamine or pyrrolidine to give the key inter-
mediates (5) (Scheme 1). In parallel, the same 5-alky-
lindole (4) was deprotonated using a Grignard reagent
and trapped with the acid chloride of Cbz-d-proline16 to
a€ord the corresponding intermediate (7). Finally, the
reduction of 5 and 7 with 4 equivalents of lithium
aluminum hydride in re¯uxing tetrahydrofuran gave the
targeted 5-alkyltryptamines (6) and 5-alkyl-3-(N-methyl-
pyrrolidin-2-yl-methyl) derivatives (8), respectively, as
®nal products suitable for biological evaluation (Table 1).
NAc
NA
440
1167
101.5
14.7
28.6
51.8
10.4
15.5
aKi values are given as the mean of at least two independent determi-
nations performed in duplicate.
bNone of the compounds demonstrated any antagonist activity with
sumatriptan as agonist.
cNot available.
0.45 nM) but poor selectivity over 5-HT1B (1.9-fold). In
line with this ®nding, we were able to demonstrate that
the 5-isopropyl substituents in 6c,18 6d and 8c were
more potent than their corresponding 5-ethyl analogues
(6a, 6b, and 8b). Similar trends were observed in going
from 5-isopropyl to the corresponding tert-butyl groups
(6d to 6e and 8c to 8d). However, in contrast to the
previous ®nding of poor selectivity with MBT, the use of
larger tertiary amine side chains provided much greater
binding selectivity for 5-HT1D. Compounds in each
amine side chain series ((i) 6a and 6c; (ii) 6b, 6d and 6e;
(iii) 8a±d)) showed better selectivities (17.8 to 125-fold)
The binding anities of 5-alkylindole derivatives (6a±e
and 8a±d) and sumatriptan have been determined at the
cloned human 5-HT1D and 5-HT1B receptors. Most of
these compounds exhibited very high binding anities for
the human 5-HT1D receptor compared to sumatriptan,
with improved 5-HT1B/5-HT1D selectivity (Table 1). It has
been recently shown that the steric size of the lipophilic
substituent at the 5-position of indole has a signi®cant
impact on the 5-HT1D anity, with enhanced potency
as the size increased.17 For example, N-methyl-5-tert-
butyltryptamine (MBT) showed very potent binding (Ki

A. Slassi et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1707±1709
1709
than sumatriptan (8.7-fold), with a general trend for
increasing selectivity with increasing size of alkyl group
(Et, iPr, tBu).
9. Rebeck, G. W.; Maynard, K. I.; Hyman, B. T.; Moskowitz,
M. A. Proc. Natl. Acad. Sci. USA 1994, 91, 3666.
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The functional activities of selected compounds (6d, 6e,
8a±8d and sumatriptan) were evaluated both as antago-
nists and as agonists using isolated rabbit saphenous vein
(RSV) preparation as measures of functional activity. All
compounds showed agonist activity with EC50 values
(Table 1), with no demonstrated antagonist activity.
In summary, a series of highly potent and selective 5-
alkyltryptamine derivatives have been developed using a
variety of tertiary amine side chains. The constrained
analogues derived from d-proline provided several com-
pounds with subnanomolar potency and high selectivity.
Compound 6e is currently being further evaluated in
animal models for the treatment of migraine.
14. (a) Glennon, R. A.; Hong, S.; Bondarev, M.; Law, H.;
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K. H.; Kamboj, R.; McCallum, K.; Mazzocco, L.; Dyne, K.;
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