N-[ω-[4-(2-methoxyphenyl)-1-piperazinyl]alkyl]-2-quinolinamines as high-affinity fluorescent 5-HT1A receptor ligands

Article abstract of DOI:10.1021/jm7013919

We here report on the design, synthesis, binding affinities, and fluorescent properties of a series of serotonin 5-HT_1A receptor ligands, with N-[ω-[4-(2-methoxyphenyl)-1-piperazinyl]alkyl]-2- quinolinamine structure. Several of the new ligands

Full text of DOI:10.1021/jm7013919

1492
J. Med. Chem. 2008, 51, 1492–1495
N-[ω-[4-(2-Methoxyphenyl)-1-piperazinyl]alkyl]-2-quinolinamines as High-Affinity Fluorescent
5-HT1A Receptor Ligands
Enza Lacivita* and Marcello Leopoldo
Dipartimento Farmaco-Chimico, UniVersità degli Studi di Bari, Via Orabona, 4, 70125 Bari, Italy
ReceiVed NoVember 6, 2007
We here report on the design, synthesis, binding affinities, and fluorescent properties of a series of serotonin
5-HT1A receptor ligands, with N-[ω-[4-(2-methoxyphenyl)-1-piperazinyl]alkyl]-2-quinolinamine structure.
Several of the new ligands displayed nanomolar affinity at 5-HT1A receptor and good fluorescent properties.
In particular, derivative 24 showed a favorable combination of 5-HT1A receptor affinity (Ki ) 0.4 nM),
Stokes shift (excitation wavelength ) 381 nm, emission wavelength ) 455 nm), and quantum yield in
ethanol (Φ ) 0.45).
Chart 1. Structures of 5-HT1A Receptor Agents
Introduction
Fluorescence spectroscopy is becoming a valuable addition
to the array of techniques available for real time direct visualization
of fluorescent ligand–receptor interactions in biological systems.
For instance, scanning confocal microscopy,1–3 fluorescence
correlation spectroscopy,4,5 and two-photon fluorescence laser
scanning microscopy6,7 allow the noninvasive imaging and
quantification of these interactions in single living cells under
a wide variety of experimental conditions. Moreover, fluores-
cence polarization techniques have been used in analytical and
clinical chemistry as versatile screening alternatives with greatly
reduced environmental and cost impacts compared with radio-
ligand assays.8
The serotonin-1A (5-HT1A) receptor is an important member
of the large family of serotonin receptors, and it is perhaps the
most extensively studied for a number of reasons. One of the
main reasons is the availability of the selective agonist 8-OH-
DPATa that has allowed extensive biochemical, physiological,
and pharmacological characterization of the receptor. The
5-HT1A receptor was the first among all the serotonin receptors
to be cloned and sequenced. The human, rat, and mouse 5-HT1A
receptors have been cloned and their amino acid sequences
deduced. More importantly, the receptor has been stably
expressed in a number of neural and non-neural cell lines.
Furthermore, it was the first serotonin receptor for which
polyclonal antibodies were obtained, allowing their visualization
at the subcellular level in various regions of the brain.9 Starting
in the mid-1980s, the 5-HT1A receptor has been the object of
intense study which culminated in the introduction into the
market of the 5-HT1A receptor partial agonist buspirone (1) as
an anxiolytic (Chart 1).10 Other 5-HT1A agents have demon-
strated a role for the 5-HT1A receptor in various pathologies.
For instance, the mixed 5-HT1A/D2 agents bifeprunox (2)11 and
SLV308 (3)12 have been studied for the treatment of schizo-
phrenia and Parkinson’s disease, respectively; vilazodone (4),13
a 5-HT1A partial agonist/serotonin reuptake inhibitor, has been
proposed as a fast-acting antidepressant, as well as the 5-HT1A
antagonist robalzotan (5);14 xaliproden (6)15 and repinotan (7)16
have been investigated as neuroprotective agents. Very recently,
the 5-HT1A receptor agonist F 13640 (8) underwent phase II
clinical trials for the treatment of severe, chronic pain.17
Therefore, after two decades of research, the 5-HT1A receptor
is still under active investigation.
Several structurally different compounds are known to bind
5-HT1A receptor.18 Among these, a large number of N1-
substituted N4-arylpiperazines (the so-called “long-chain” arylpip-
erazines) have been extensively studied. The general formula
of these compounds presents an 1-arylpiperazine linked through
an alkyl chain of variable length to a terminal fragment,
belonging to one of the following four structural classes: (i)
imides, (ii) amides, (iii) alkyl, arylalkyl, or heteroarylalkyl
derivatives, and (iv) tetralins.19 During the course of our studies
we have published several papers dealing with the synthesis
and structure-affinity relationships elucidation of “long-chain”
arylpiperazines as 5-HT1A receptor ligands.20,21
* To whom correspondence should be addressed. Phone: +39-080-
5442750. Fax: +39-080-5442231. E-mail: lacivita@farmchim.uniba.it.
a Abbreviations: 8-OH-DPAT, 8-hydroxy-N,N-dipropylaminotetraline;
GPCR, G-protein-coupled receptor; BODIPY, dipyrromethene boron
difluoride.
10.1021/jm7013919 CCC: $40.75
2008 American Chemical Society
Published on Web 02/13/2008

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5 1493
Table 1. Binding Affinities of Ligands 9–22, and 24 for Serotonin
5-HT1A Receptor and Their Fluorescence Properties in Ethanol
materials were purchased from commercial sources or prepared
according to literature, as detailed in the Experimental Section.
Results and Discussion
The affinity values for serotonin 5-HT1A receptor and
fluorescent properties of the target compounds are displayed in
Table 1. Derivative 9 possessed good binding affinity for 5-HT1A
receptor and quite low fluorescent emission. Therefore, we
performed structural modifications with the aim to improve both
properties. It is well documented that the fluorescence emission
of aromatic substances containing a nitro group is generally
weak, primarily as a result of large non radiative decay from
the excited state.29 On the other hand, it has been reported that
an electron-donating group such as methoxy (having inductive
+I and resonance +M effects) can increase fluorescence
emission.30 On the basis of such considerations, the unsubsti-
tuted quinoline 10 was prepared as well as the 6-methoxy- and
7-methoxyquinolines 14 and 18, respectively. These latter
compounds would allow us to evaluate the effect of conjugation
on fluorescence emission. As far as the affinity for 5-HT1A
receptor was concerned, we tested derivatives 10, 14, and 18
and their homologues 11–13, 15–17, and19–21 bearing an alkyl
chain from three to five methylene units because optimization
of the intermediate alkyl chain length is a key step when
studying “long-chain” arylpiperazines. Considering the fluo-
rescent properties of 10, it can be observed that removal of nitro
group from 9 resulted in an enhancement of fluorescent
emission. The nitro group replacement in 9 by the methoxy
substituent (compound 14) resulted in a considerable increase
of Φ value (0.09 vs 0.52). Shifting of the methoxy from 6- to
7-position (compounds 14 and 18) diminished fluorescence
emission (Φ ) 0.52 and 0.14, respectively). Elongation of the
alkyl chain length of 10, 14, and 18 increased fluorescence
emission, which was more evident for the unsubstituted quino-
lines 11–13 and for the 7-methoxyquinolines 19–21. These
results confirmed that introduction of a methoxy group on the
aromatic ring can increase fluorescence, especially when
conjugation of π-system was extended. Moreover, compounds
with a four methylene chain (12, 16, and 20) showed higher
quantum yields than their respective homologues. Finally,
compounds 10–21 showed high difference of excitation to
emission maximal wavelengths (Stokes shift).
Ki,
excitation emission
compd
R1
R2
n
nM ( SEMa λmax (nm) λmax (nm)
Φ
9
NO2
H
H
H
H
OCH3
OCH3
OCH3
OCH3
H
H
H
H
CH3
NH2
H
H
H
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
H
2
2
3
4
5
2
3
4
5
2
3
4
5
4
4
14.2 ( 2.7b
33 ( 4
13 ( 1
9.7 ( 0.3
0.030 ( 0.008
28 ( 2
22.0 ( 0.8
0.20 ( 0.05
2.6 ( 0.8
2.1 ( 0.4
0.20 ( 0.06
4.6 ( 0.2
0.50 ( 0.05
0.54 ( 0.01
0.38 ( 0.02
5.1 ( 0.5
271
343
342
341
347
362
360
359
360
361
358
365
362
346
381
450
406
405
390
392
405
408
405
410
381
380
382
380
400
455
0.09
0.17
0.30
0.46
0.35
0.52
0.52
0.54
0.53
0.14
0.47
0.49
0.45
0.20
0.45
10
11
12
13
14
15
16
17
18
19
20
21
22
24
H
8-OH-DPAT
2-aminopyridine
290
353
0.37
a The values are the mean ( SEM from three independent experiments
in triplicate. b Data taken from ref 28.
Recently, we embarked on a research program to develop
high affinity fluorescent ligands for certain GPCR,22 including
the 5-HT1A receptor.
Fluorescent probes have been prepared by labeling a ligand
with a fluorophore, such as fluorescein,3 BODIPY,23 coumarin,24
and dansyl,25 into an area of the structure that would have
minimal influence on biological activity. However, this structural
modification has been reported to cause variations of lipophi-
licity, affinity, selectivity, and intrinsic activity.26,27
For our purpose, we have envisaged a different strategy by
including the fluorescent core into a framework endowed with
affinity for the target receptor. In this way, it is possible
overcome the above-mentioned shortcomings and allow access
to an entire series of fluorescent ligands with the possibility to
optimize the fluorescence properties and receptor affinity at the
same time.22
As far as the 5-HT1A receptor affinity is concerned, the
analogues 10 and 14 displayed similar affinity as 9, whereas
18 was slightly more potent than the nitro derivative 9.
Elongation of the alkyl chain of 10, 14, and 18 had a beneficial
effect on 5-HT1A receptor affinity. In fact, compounds 13 (n )
5), 16 (n ) 4), 19 (n ) 3), and 21 (n ) 5) displayed affinities
in the subnanomolar range. However, a general trend did not
emerge because maximum 5-HT1A receptor affinity was shown
by compounds with different linker length.
Taken together, 5-HT1A receptor affinity data and fluorescence
properties indicated that the pursued optimization strategy was
successful, especially for derivative 16 which showed the highest
Φ value within this series and very high 5-HT1A receptor affinity
(Ki ) 0.20 nM).
We have focused our attention on N-[2-[4-(2-methoxyphenyl)-
1-piperazinyl)ethyl]-6-nitro-2-quinolinamine (9, Table 1) that
we reported as mixed serotonin transporter/5-HT1A receptor
ligand (5-HT1A Ki ) 14.2 nM).28 In particular, we wondered if
9 was fluorescent because the 2-quinolinamine moiety closely
resembles that of 2-aminopyridine, which is one of the
fluorescent standards used for quantum yield determination
(Table 1). Actually, 9 demonstrated to be fluorescent (Table
1), and therefore, it represented our starting point to develop
fluorescent 5-HT1A receptor ligands. Subsequent structural
modifications of 9 were performed with the twofold aim to
increase both 5-HT1A receptor affinity and fluorescent emission.
Finally, we wanted to explore if other electron donating
substituents in 6-position (i.e., methyl or amino) would have
beneficial effect on fluorescence. Methyl derivative 22 showed
worst fluorescence properties than 16 because of lower excitation
and emission wavelengths and lower quantum yield, whereas
the amino derivative 24 (Figure 1) retained acceptable quantum
yield and displayed excitation and emission maximum at higher
wavelengths than 16. Moreover, compounds 22 and 24 dem-
onstrated to be as potent as 16 at 5-HT1A receptor.
Chemistry
The target compounds were prepared according to Scheme
1. Final compounds 10–22 were prepared by condensing
2-chloroquinolines 25a-d with the appropriate amine 26a-d.
Target compound 24 was obtained as follows: 2-chloro-6-
nitroquinoline (25e) reacted with amine 26d to give nitro
derivative 23, which was hydrogenated to afford 24. The starting

1494 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5
Brief Articles
Scheme 1a
a Reagents: (A) heated at 150 °C; (B) H2, Pd/C 10%.
by chromatography (CHCl3/CH3OH, 19:1 as eluent) giving the
expected compound as pale yellow oil.
N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]-6-methoxy-
2-quinolinamine (16): 22% yield; GC-MS m/z 421 (M+ + 1, 4),
1
420 (M+, 8), 258 (100), 227 (30); H NMR (CDCl3) δ 1.71–1.74
(m, 4H), 2.52 (t, 2H, J ) 6.9 Hz), 2.71 (br s, 4H), 3.14 (br s, 4H),
3.45–3.51 (m, 2H), 3.86 (s, 3H), 3.86 (s, 3H), 5.19 (br s, 1H, D2O
exchanged), 6.64 (d, 1H, J ) 8.8 Hz), 6.85–7.03 (m, 5H), 7.20
(dd, 1H, J ) 2.7 Hz, 9.1 Hz), 7.61 (d, 1H, J ) 9.1 Hz), 7.74 (d,
1H, J ) 8.8 Hz). The hydrochloride salt melted at 94–97 °C (from
CH3OH/Et2O). Anal. (C25H32N4O2 ·4HCl) C, H, N.
6-Amino-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-2-
quinolinamine (24). Nitro derivative 23 (0.32 g, 0.73 mmol) was
dissolved in ethanol and hydrogenated at normal pressure and room
temperature in the presence of 10% Pd/C (0.1 g) until the uptake
ceased. The catalyst was removed by filtration through Celite, and
the solvent was evaporated in vacuo to give a crude residue that
was chromatographed (CHCl3/CH3OH, 9:1, as eluent) to provide
pure compound 24 as a pale-brown solid (0.140 g, 47% yield):
GC-MS m/z 405 (M+, 3), 243 (100), 212 (27), 159 (36); 1H NMR
(CDCl3) δ 1.74 (app t, 4H), 2.53 (app t, 2H), 2.74 (br s, 4H), 3.15
(br s, 4H), 3.46–3.49 (m, 2H), 3.65 (br s, 2H, D2O exchanged),
3.86 (s, 3H), 5.60 (br s, 1H, D2O exchanged), 6.65 (d, 1H, J ) 9.1
Hz), 6.81–7.05 (m, 6H), 7.57 (d, 1H, J ) 8.8 Hz), 7.68 (d, 1H, J
) 8.8 Hz); mp 97 °C dec (from CHCl3/n-hexane). Anal.
(C24H31N5O) C, H, N.
Fluorescence Spectroscopy. Emission and excitation spectra of
compounds 9-22 and 24 were recorded as detailed in the
Supporting Information. Fluorescence quantum yields were calcu-
lated in reference to that of 2-aminopyridine in ethanol as a standard
(excitation wavelength 285 nm; Φ ) 0.37),29 according to Demas
et al.32
Figure 1. Excitation and emission spectra of compound 24 in ethanol.
Next, we studied the intrinsic activity of compounds 16 and
24 because fluorescent agonists or antagonists provide different
information on receptor trafficking. The intrinsic activity at
5-HT1A receptor of 16 and 24 was assessed in an isolated guinea-
pig ileum assay.31 Both compounds displayed agonistic proper-
ties at 5-HT1A receptor. In fact, the derivative 16 acted as a full
agonist (EC50 ) 34.4 ( 7.0 µM), and its activity was reverted
by the 5-HT1A receptor antagonist WAY-100635 in a dose-
dependent manner (pA2 ) 7.94 ( 0.79), whereas 24 behaved
as a partial agonist (81% of the maximal response, EC50 ) 62.1
( 3.5 µM).
Conclusions
We have identified a series fluorescent ligands for 5-HT1A
receptors from the structural modifications of the weakly
fluorescent 5-HT1A ligand N-[2-[4-(2-methoxyphenyl)-1-piper-
azinyl)ethyl]-6-nitro-2-quinolinamine (9). Several of the newly
prepared ligands displayed nanomolar affinity at 5-HT1A receptor
and fluorescent properties suitable for use in two-photon
microscopy, being their excitation wavelengths within the
excitation range of lasers currently available (720–880 nm). In
particular, the fluorescent ligand 24 showed a favorable
combination of 5-HT1A receptor affinity (Ki ) 0.4 nM), Stokes
shift (excitation wavelength ) 381 nm, emission wavelength
) 455 nm), and quantum yield in ethanol (Φ ) 0.45).
Fluorescence visualization experiments in cell lines expressing
5-HT1A by two photon laser microscopy are in due course.
Supporting Information Available: Spectral data of compounds
10–15, 17–23. Biological methods and statistical analysis. Elemental
analysis data of compounds 10–22 and24. Experimental procedure
for fluorescence spectroscopy. This material is available free of
charge via the Internet at http://pubs.acs.org.
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JM7013919