Pyrrolo[3,2,1-ij]quinoline derivatives, a 5-HT(2c) receptor agonist with selectivity over the 5-HT(2a) receptor: Potential therapeutic applications for epilepsy and obesity

Article abstract of DOI:10.1016/S0960-894X(00)00141-4

A series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized, evaluated for their activity against the 5-HT(2c) and 5-HT(2a), receptors and found to be agonists at 5-HT(2c) with selectivity over 5-HT(2a). (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00141-4

Bioorganic & Medicinal Chemistry Letters 10 (2000) 919±921
Pyrrolo[3,2,1-ij]quinoline Derivatives, a 5-HT2c Receptor Agonist
with Selectivity over the 5-HT2a Receptor: Potential Therapeutic
Applications for Epilepsy and Obesity
Methvin Isaac,* Abdelmalik Slassi, Anne O'Brien, Louise Edwards, Neil MacLean,
Donna Bueschkens, David K. H. Lee,y Kirk McCallum, Ines De Lannoy,y
Lidia Demchyshyn and Rajender Kamboj
NPS Allelix Corp., 6850 Goreway Drive, Mississauga, ON, Canada L4V 1V7
Received 14 December 1999; accepted 16 February 2000
AbstractÐA series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized, evaluated for their activity against the 5-HT2c and 5-
HT2a, receptors and found to be agonists at 5-HT2c with selectivity over 5-HT2a. # 2000 Elsevier Science Ltd. All rights reserved.
5-Hydroxytryptamine (5-HT or serotonin), a key neu-
rotransmitter of the peripheral and central nervous sys-
tem (PNS and CNS), has been implicated in a variety of
sensory, motor, and behavioral processes. The diverse
e€ects of this neurotransmitter are related to the exten-
sive projections of serotonergic neurons throughout the
brain and the large number of distinct serotonin recep-
tor subtypes. At least 14 distinct serotonin receptor
subtypes are expressed in the mammalian CNS.1 The
contribution of these receptors to the action of ser-
otonin has been dicult to ascertain owing to the pau-
city of selective pharmacological agents.
functional receptor genes.3 This strategy has been
applied to the study of 5-HT2c receptor function. 5-
HT2c receptors are expressed in many brain regions (the
limbic structures, extrapyramidal motor pathways,
hypothalamus, thalamus, and monoaminergic cell
groups) and have been implicated in the regulation of
food intake and anxiety.4 For example, the non-selective
5-HT2c receptor agonist, m-chlorophenylpiperazine 1
(mCPP), produces hypophagic and anxiogenic e€ects
that were attenuated by 5-HT2c receptor antagonists
(Fig. 1).5 Recently, the novel potent and preferential 5-
HT2c receptor agonist 2 has been shown to mediate the
prototypical behavioral response of penile erection.6
Although these studies implicated the 5-HT2c receptors
in the modulation of feeding and anxiety, elucidation of
the functional roles of these receptors has been hindered
by a limited availability of selective agents. In addition,
such paucity of selective agents can be attributed to
the fact that the 5-HT2c receptors share substantial
sequence homology with the 5-HT2a receptor.
The 5-HT2 subfamily of serotonin receptors is composed
of three subtypes, the 5-HT2a, 5-HT2b, and 5-HT2c
receptors. All three receptors couple to the activation of
the inositol phosphate and diacyl glycerol pathways via
the G-protein, Gq/11.1 Recently, other second messenger
systems have been shown to be regulated by 5-HT2 sti-
mulation, including mitogen activated protein kinase
(MAP-kinase).2 The limited access to selective pharma-
cological tools amongst the 5-HT2 subfamily of ser-
otonin receptors has led to the use of gene targeting
techniques to generate mouse lines that selectively lack
Through library screening along with synthetic chemistry,
we have developed a class of human 5-HT2c receptor
agonists that have good to moderate selectivity over
the human 5-HT2a, receptor. This paper describes the
synthesis, structure±activity relationship and in vitro
pharmacology of a series of pyrrolo[3,2,l-i,j]quinoline
derivatives. These selective compounds o€er the possi-
bility of a novel approach to the treatment of obesity
and epilepsy.
*Corresponding author. Tel.: +1-905-677-0831; fax: +1-905-677-
9595; e-mail: misaac@allelix.com
yCurrent address: Maxxam BioDiscoveries Inc., 101 Resources Road,
Toronto, ON, Canada M9P 3T1.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00141-4

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M. Isaac et al. / Bioorg. Med. Chem. Lett. 10 (2000) 919±921
Pharmacological Testing
Compounds 7a±e and 8 were evaluated in vitro for their
5-HT2c and 5-HT2a receptor binding anity (Table 1).
Membranes prepared from HEK-293 cells stably
expressing the 5-HT2a or 5-HT2c receptor were incu-
bated with 3H-ketanserin (5-HT2a receptor) or 3H-
mesulergine (5-HT2c receptor) and increasing con-
centrations of test compounds. Estimated Ki values of
each test compound were subsequently determined for
both receptor subtypes. Functional agonist activity was
determined by a ¯uorescence-based assay measuring
intra-cellular calcium mobilization for both 5-HT2a and
5-HT2c receptor cell lines (Table 1).
Figure 1. 5-HT2 agonists.
Chemistry
The pyrrolo[3,2,1-ij]quinolin-1-yl ethylamine deriva-
tives,7 7a±e, were synthesized as shown in Scheme 1.
Nitrosation of the 1,2,3,4-tetrahydroquinolines 3 with
NaNO2 and H2SO4 at 0 ꢀC, followed by reduction with
LiAlH4, a€orded the corresponding 1-amino-1,2,3,4-
tetrahydroquinoline 4. Subsequent Fischer indole cycli-
zation with either 4-chlorobutanal 5, or 5-chloropentan-2-
one 6, in re¯uxing aqueous methanol (MeOH:H2O=9:1)
gave the compounds 7a±e in moderate to good yields.
The N-methyl derivative 8 was synthesized from 7c in
two steps by treatment with (Boc)2O followed by
reduction with LiAIH4 (Scheme 1).
Results and Discussion
The pyrrolo[3,2,l-ij]quinoline derivative 7a, with a sim-
ple tricyclic core and an ethylamine side chain, was
identi®ed as a 5-HT2c receptor ligand from library
screening. This compound showed moderate 5-HT2c
receptor anity (Ki=41 nM) with a 19-fold selectivity
over the 5-HT2a receptor. In contrast, the 2-methyl
Scheme 1. Reagents: (a) NaNO2, H2SO4, 0±5 ꢀC; (b) LIA1H4, ether; (c) 5 or 6, MeOH (aq), re¯ux; (d) (Boc)20, NaOH; (e) LiAlH4, THF.
Table 1. In vitro activity of pyrrolo[3,2, 1-i,j]quinolin- 1-yl ethylamines at the h5-HT2a and h5-HT2c receptors
Compound
Binding activity
Binding ratio
Functional activity (agonist)
5-HT2c (Kia) nM)
5-HT2a (Kia nM)
5-HT2a/5-HT2c
5-HT2c (EC50, nM)
5-HT2a (EC50, nM)
7a
7b
7c
7d
7e
8
41
225
18
194
47
794
676
2340
954
631
1458
19.4
3.0
130
4.9
13.4
44
0.20b
9.0b
5.7c
145b
Ð
269b
41c
Ð
348b
>10,000d
0.23b
180c
33
aKi values are given as the mean of at least two independent determinations performed in triplicate.
bFull agonist with no antagonist activity.
cPartial agonist only.
dAntagonist with 1.1 mM EC50
.

M. Isaac et al. / Bioorg. Med. Chem. Lett. 10 (2000) 919±921
921
derivative 7b showed lower 5-HF2c, receptor anity
than 7a with a signi®cant loss of 5-HT2c, receptor
selectivity. Compound 7c (R=Me, R0=F, X=C) having
an 8-¯uoro substituent along with a 4-methyl group was
found to be very potent and selective. The presence of two
substituents in 7c signi®cantly increased both 5-HT2c,
receptor anity (Ki=18 nM) and 5-HT2a/5-HT2c, recep-
tor selectivity (130-fold). However, as in the case of 7b,
the presence of a 2-methyl substituent in 7d resulted in
loss of both 5-HT2c, receptor anity (Ki=194 nM) and
selectivity (5-fold) compared to 7c. The introduction of
an N-methyl group onto the amino side chain (i.e., from
7c to 8) lead to a slight decrease in both 5-HT2c, recep-
tor anity for 8 (Ki=33 nM) and selectivity (44-fold).
The substitution of a carbon atom for a heteroatom (i.e.
C to S) in the quinoline ring system along with an 8-
chloro substituent gave derivative 7e (Ki=47 nM,
selectivity 13-fold). This compound did not show any
improvement when compared to the lead compound 7a.
and functionally selective ligands thus making them
promising candidates for the prophylactic management
of epilepsy and obesity. Moreover, compound 7c was
racemic with a chiral center at C-4, thus separation of the
enantiomers may show that one enantiomer has a higher
anity at the 5-HT2c receptor than its antipode. E€orts
are currently under way to resolve these enantiomers.
References and Notes
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cellular calcium mobilization in HEK-293 cells expres-
sing the 5-HT2c and 5-HT2a receptors, indicated that
all compounds demonstrated agonist activity at the 5-
HT2c receptor. More interestingly, compounds 7a, 7b
and 7e were all found to be full agonists (EC50 of 0.20,
9.0 and 0.23 nM, respectively) with very good functional
selectivity over the 5-HT2a, receptor (Table 1).
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In conclusion, the pyrrolo[3,2,1-ij]quinoline derivatives
7a±e and 8 were all found to be agonists at the 5-HT2c
receptor in vitro. The derivatives 7c and 7e were potent