Indolebutylamines as selective 5-HT1A agonists

Article abstract of DOI:10.1021/jm040792y

A series of new 1-[4-(indol-3-yl)butyl]-4-arylpiperazines was prepared to identify highly selective and potent 5-HT_1A agonists as potential pharmacological tools in studies of mood disorders. The combination of structural elements (indole-alkyl

Full text of DOI:10.1021/jm040792y

J . Med. Chem. 2004, 47, 4677-4683
4677
In d olebu tyla m in es a s Selective 5-HT1A Agon ists
Timo Heinrich,* Henning Bo¨ttcher, Gerd D. Bartoszyk, Hartmut E. Greiner, Christoph A. Seyfried, and
Christoph van Amsterdam
Preclinical Pharmaceutical Research, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany
Received February 23, 2004
A series of new 1-[4-(indol-3-yl)butyl]-4-arylpiperazines was prepared to identify highly selective
and potent 5-HT1A agonists as potential pharmacological tools in studies of mood disorders.
The combination of structural elements (indole-alkyl-amine and aryl-piperazine) known to
introduce 5-HT1A receptor affinity and the proper selection of substituents (R on the indole
moiety and R′ on the aryl moiety) led to compounds with high receptor specificity and affinity.
In particular, the introduction of the methyl ether or the unsubstituted carboxamide as
substituents in position 5 of the indole (R) guaranteed serotonergic 5-HT1A affinity compared
to the unsubstituted analogue. Para-substituted arylpiperazines (R′) decreased dopaminergic
D2 binding and increased selectivity for the 5-HT1A receptor. Agonistic 5-HT1A receptor activity
was confirmed in vivo in the ultrasonic vocalization test, and the results suggest that the
introduction of the carboxamide residue leads to better bioavailability than the corresponding
methyl ether. 3-{4-[4-(4-Carbamoylphenyl)piperazin-1-yl]butyl}-1H-indole-5-carboxamide 54
was identified as a highly selective 5-HT1A receptor agonist [GTPγS, ED50 ) 4.7 nM] with
nanomolar 5-HT1A affinity [IC50 ) 0.9 nM] and selectivity [D2, IC50 > 850 nM]. 3-{4-[4-(4-
Methoxyphenyl)piperazin-1-yl]butyl}-1H-indole-5-carboxamide 45 is one of the most potent and
selective 5-HT1A agonists known [5-HT1A, IC50 ) 0.09 nM; D2, IC50 ) 140 nM].
Ch a r t 1
In tr od u ction
Diseases of the central nervous system are often
correlated with a malfunction of the dopaminergic (e.g.,
schizophrenia, Parkinsonism) and/or serotonergic (e.g.,
anxiety, depression) system. Although in some cases
treatment is available with drugs targeting the men-
tioned neurotransmitter systems without a specific
selectivity, therapy is far from being satisfactory. The
search for discriminating ligands is a thoroughly con-
sidered approach in medicinal chemistry for a better
understanding of serotonin (5-HT) and dopamine (D)
receptor subtypes in mood disorders. Among the 5-HT
receptors, the 5-HT1A receptor subtype is the best
studied and several classes of agents are known to
interact with high affinity. Aminotetralines1 with 8-OH-
DPAT as the most prominent member and arylpipera-
zines2 with the spirone class of compounds (e.g., ipsa-
pirone3) have been extensively evaluated (Chart 1).4
Besides these, additional different chemical classes such
as indolylalkylamines,5 ergolines, aporphines and aryl-
oxyalkylamines have been investigated.4 We entered
into the field with the discovery that the indolealkyl-
amine roxindole 1 is not only a dopamine but also a
potent 5-HT1A receptor agonist. Classic indolealkyl-
amines such as 5-CT show no selectivity for a distinct
5-HT receptor subtype like the endogenous neurotrans-
mitter 5-HT itself. Published efforts to improve selectivi-
ty and affinity of derivatives of 5-HT and 5-CT were not
successful so far.2,4,6 To elucidate whether it is possible
to find compounds in the structural class of roxindole,
with selectivity for the 5-HT1A receptor and devoid of
dopamine receptor affinity, we first recall the structural
elements responsible for the dopamine receptor interac-
tion.
As published previously7 within the indolealkylamine
class of roxindole, a set of four structural elements was
found to be essential for high-affinity agonism at the
D2 autoreceptor: (1) the aryl unsubstituted 4-phenyl-
1,2,3,6-tetrahydropyridine, (2) the double bond and the
basic center of the tetrahydropyridine, (3) the saturated
four-carbon chain linking the basic nitrogen with the
3-indole position, and (4) the indole heterocycle unsub-
stituted in positons 1, 2, and 7.8
Besides dopamine receptor affinity (D2, IC50 ) 5.6 nM)
* To whom correspondence should be addressed. Phone: ++49 (0)
6151 72 65 89. Fax: ++49 (0) 6151 72 31 29. E-mail: timo.heinrich@
merck.de.
roxindole 1 shows nanomolar 5-HT1A binding (5-HT1A
,
IC50 ) 0.8 nM) as full agonist (GTPγS, ED50 ) 5 nM)
10.1021/jm040792y CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/10/2004

4678 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19
Heinrich et al.
Sch em e 1a
displace [3H]spiperone (dopamine antagonist)18 in rat
striatal membranes or cloned human receptors. Sero-
tonergic 5-HT1A activity of the compounds was mea-
sured in rat hippocampal membranes with [3H]-8-OH-
DPAT as ligand.17 The intrinsic activity of the compounds
as 5-HT1A agonist or antagonist was tested in the
GTPγS assay with recombinant human 5-HT1A recep-
tors stably expressed in membranes of Chinese hamster
ovary (CHO) cells.19 The 5-HT1A agonistic activity in
vivo was determined by the ability of the compounds to
inhibit ultrasonic vocalization in rats.20
a
(a) AcCN; (b) NMP, TEA 6.
Sch em e 2a
Resu lts a n d Discu ssion
First, to avoid phase II metabolism of roxindole 1,10
we examined closely related indolebutylamines with the
alkylated 5-hydroxy function on the indole (Table 1). The
methyl ether 10 shows decreased 5-HT1A binding affin-
ity in comparison to 1, but the introduction of oxygen
functionality on the aromatic substituent on THP (11-
13) reinstalls 5-HT1A binding and further diminishes D2
affinity (vide infra). This structural relationship points
to a possible cooperative effect of substituents on the
indole and the second aryl group with regard to the
5-HT1A receptor affinity.21
a
(a) NaOH, dioxane; (b) 1-methyl-2-chloropyridinium iodide,
NH3. R ) phenylpiperidine or phenylpiperazine.
and nanomolar 5-HT reuptake inhibition (RUI, IC50
)
1.4 nM).7d In addition to these predominant affinities,
roxindole binds fairly well to a couple of other targets
too and shares a multireceptor activity profile like most
successful antipsychotics of the past and the present.9
To further exploit the potential of these indolebutyl-
amines, it was decided to elucidate the possibility of
preparing more selective compounds in this class.
Furthermore, to receive bioavailable drug candidates,
we wanted to avoid structural elements that could be
target of phase II metabolism at the 5-hydroxyindole
group of roxindole.7,10
Ta ble 1. Roxindole and Close Analogues (IC50 ( SEM (nM))a
It soon turned out to be difficult to suppress seroto-
nergic activities in order to obtain more selective
dopamine agonists. In contrast, suppression of dopam-
inergic activity to yield selectivity for the 5-HT receptor
subtype 1A seemed to be feasible and became the focus
of our interest as presented subsequently.
compd
R
R′
R′′
5-HT1A
D2
1
10
11
12
13
OH
H
H
OH
H
H
H
H
0.8 ( 0.1
20 ( 9
0.4 ( 0.2
0.6 ( 0.1
0.4 ( 0.3
5.6 ( 0.4
20 ( 5.4
OCH3
OCH3
OCH3
OCH3
∼100
OCH3
OCH2CH2O
>100
>100
a
IC50 values were obtained from 5 to 10 concentrations of the
compound, each in triplicate, and are defined as the concentration
(nM) resulting in 50% inhibition of binding.
Ch em istr y
The synthetic pathway to the 4-phenyl-1,2,3,6-tet-
rahydropyridines (THP) from Table 1 has already been
published.8 The piperidines listed in Table 2 were
obtained by hydrogenation of the appropriate tetrahy-
dropyridines following a known literature synthesis
methodology.11 The piperazines 2 used to build the
compounds shown in Tables 3-5 were synthesized by
either one of the two pathways from Scheme 1, if not
commercially available.
Ta ble 2. Comparison of Piperidines and Piperazines (IC50
(
SEM (nM))a
Piperazine 4 was arylated with fluorobenzene 3 in
acetonitrile at elevated temperature12 or an aniline 5
was reacted with bis(2-chloroethyl)ammonium chloride
6 in 1-methylpyrrolidin-2-one (NMP) and a tertiary
amine.13 The compounds from Tables 2-5 were pre-
pared according to the procedure from Scheme 2 or as
previously described.14
The esters 7 were saponified under basic conditions,
and the resulting acids 8 reacted with gaseous ammonia
to the carboxamides 9 after activation with Mukaiya-
ma’s reagent.15 Direct aminolysis of the ester did not
work with our 5-indolyl esters. The synthesis of the
5-indolyl ethers (10-13, 22-42),7,14 5-indolylphenols
(14, 15),8,16 and 5-indolyl methyl esters (16, 17)11 is
known from the literature.17
compd
R
X
5-HT1A
D2
14
15
16
17
18
19
20
21
OH
C
N
C
N
C
N
C
N
1 ( 0.5
0.8 ( 0.1
20 ( 2
40 ( 23
100 ( 55
40 ( 17
0.1 ( 0.1
0.1 ( 0.2
80 ( 23
4.2 ( 4
113 ( 65
31 ( 14
1000
>100
17 ( 1.7
7 ( 0.2
CO2CH3
CO2H
CONH2
a
IC50 values were obtained from 5 to 10 concentrations of the
compound, each in triplicate, and are defined as the concentration
(nM) resulting in 50% inhibition of binding.
Because the styrene-like moiety in the aryl-THP of
roxindole was found to be solely essential for the
dopaminergic D2 binding,8 we compared structurally
similar piperidines and piperazines for further improve-
ment of the serotonergic activity (Table 2). Though there
are differences in binding affinity and selectivity be-
Biology
The affinity of the compounds toward the dopamine
D2 receptor subtype was evaluated by their ability to

Indolebutylamines as Agonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19 4679
Ta ble 3. Influence of Aryl Substitution in
5-Methoxyindolyl-3-butylpiperazines on 5-HT1A and D2 Binding
(IC50 ( SEM (nM))a
tween piperidines and piperazines with the same sub-
stitution pattern (e.g., D2 of 14 vs 15), there is no
obvious preference in one or the other heterocycle. The
carboxylic acids 18 and 19 show no dopaminergic
activity, in contrast to the previously described THP
derivative carmoxirole22 (pointing to the importance of
the unsubstituted 4-aryl-THP as the D2 pharmaco-
phore). The corresponding esters 16 and 17 are only
weakly active on both targets without any selectivity.
The most striking observation is that the hydroxy (14,
15) and the carboxamide derivatives (20, 21) show the
highest 5-HT1A receptor affinity in this series and the
values are comparable to those of the methoxy deriva-
tives (11-13) in Table 1. To scrutinize the 5-methoxy-
indoles, a larger series with modified phenyl substitu-
ents on the piperazine moiety was prepared (Table 3).
compd
22
R
5-HT1A
20 ( 3
D2
32 ( 4.6
53 ( 13
420 ( 127
>100
C6H5
23
4-OHC6H4
2 ( 0.3
4 ( 0.4
0.8 ( 0.05
30 ( 12
2 ( 0.7
1 ( 0.5
3 ( 0.5
24 ( 15
70 ( 25
60 ( 19
0.4 ( 0.1
24
4-OCH3C6H4
4-OCH2CH3C6H4
25
26
4-OCH2C6H5C6H4
220 ( 69
n.d.
27
4-O(CH2)2OCH3C6H4
4-OC(O)CH3C6H4
28
>100
As can be seen from Table 3, the core structure
5-methoxyindole with a 1-butyl-4-phenylpiperazine leads
to robust 5-HT1A binding tolerating a variety of phenyl
substituents. In contrast, the dopaminergic D2 binding
affinity is low with this scaffold as soon as the phenyl
group is substituted and this is not influenced distinc-
tively by different phenyl residues. Benzyl ether 26 and
methoxy ethoxy ether 27 are tolerated as well as the
acetyl ester 28 and acetamide 29. The same is valid even
for the more bulky tert-butyl ester 30 or the lipophilic
silyl ether 31. Further information about steric limita-
tions was available by comparison of the methoxy
derivatives 24, 32, 35, and 38. The 4-methoxy-
phenyl derivative 24 shows nanomolar binding (4 nM),
the 3,4-bis(methoxyphenyl) compound 35 is weakly
active (10 nM), but obviously the second methoxy group
can be rotated so that repulsive interactions are negli-
gible. The 3,5-bis(methyl-4-methoxy) derivative 32 seems
to have no possibility of circumventing steric obstruc-
tions by rotation, but it is still tolerated (60 nM),
whereas the even more spaciously demanding 3,4,5-
trimethoxy-substituted phenyl in compound 38 de-
creases 5-HT1A binding to 300 nM.
29
4-NHC(O)CH3C6H4
4-OC(O)C(CH3)3C6H4
4-OTBDMSC6H4
>100
32
n.d.
31
n.d.
32
3,5-(CH3)2-4-OCH3C6H2
>100
33
>100
34
2 ( 0.4
>100
35
36
3,4-(OCH3)2C6H3
10 ( 4
4 ( 1.7
100 ( 52
100 ( 29
37
0.5 ( 0.2
120 ( 49
38
3,4,5-(OCH3)3C6H2
333 ( 117
>100
a
IC50 values were obtained from 5 to 10 concentrations of the
compound, each in triplicate, and are defined as the concentration
(nM) resulting in 50% inhibition of binding. TBDMS ) tert-
butyldimethylsilyl.
Ta ble 4. Influence of Different Indole Residues on Binding in
Indolealkylamines (IC50 ( SEM (nM))a
While aryl substituents were optimized, more 5-in-
dolyl ethers and carboxylates were under closer exami-
nation. As a resumption of the work with the THP
derivatives from Table 1 (4-methoxyphenyl residue
reduces dopamine affinity) and integration of the gained
piperazine expertise, the compounds from Table 4 were
made to elucidate the influence of different indole
5-substituents on the receptor binding profile.
compd
R
5-HT1A
D2
39
40
41
42
43
44
45
OCH2CH3
O(CH2)4CH3
OCH(CH2)4
OCH2C6H5
OC(O)CH3
CO2CH3
2 ( 0.6
200 ( 175
90 ( 5
300 ( 170
>100
>100
>100
>100
>100
The larger alkyl and alkaryl ethers as indole residues
(39-42) show only moderate binding affinity to both
5-HT1A and D2 receptors. Nevertheless, it is interesting
to see that the derivatives with two small alkyl ether
substituents (24, 25, and 39) show nanomolar or even
subnanomolar 5-HT1A receptor binding and selectivity
of a factor of 100. The observed high affinity of the
indolyl-5-carboxamides 20, 21, and 45 motivated us to
evaluate the 5-HT1A receptor binding potential of this
scaffold by preparing and examining a series of indolyl-
5-carboxamides with various aryl substituents on the
piperazine moiety (Table 5).
34 ( 23
0.5 ( 0.3
8 ( 1
CONH2
0.09 ( 0.09
140 ( 23
a
IC50 values were obtained from 5 to 10 concentrations of the
compound, each in triplicate, and are defined as the concentration
(nM) resulting in 50% inhibition of binding.
electronic requirements of the phenyl at the piperazine
ring for this receptor are negligible. Electron-rich (45,
46, 48-53) as well as electron-poor (54-58), lean (21),
and bulky (59) aromatic systems are accepted. Because
of their excellent 5-HT1A receptor potency and D2
receptor selectivity, the bis-carboxamide 54 and the
acetanilide 56 were tested for their affinity to other
G-protein-coupled receptors (GPCRs). Compound 54
shows good 5-HT1A receptor selectivity versus further
As can be seen from Table 5, the indolyl-5-carbox-
amide is an optimal structural element to enhance
5-HT1A receptor binding. Independent from the phenyl
substitution, nanomolar or even subnanomolar binding
affinities could be reached. Obviously the steric and

4680 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19
Heinrich et al.
Ta ble 5. Receptor Binding Profile of Indolyl-5-carboxamide
Derivatives (IC50 ( SEM (nM))
ether 29. Taking these results together, it can be
concluded that in general the 5-indolylcarboxamides
show higher 5-HT1A affinity than the corresponding
5-methoxyindoles.
The results from Table 1 (1, 10 vs 11-13) suggest that
the introduction of substituents on the phenyl ring
decreases D2 binding, but obviously the position of the
substituents is very important. In most cases (e.g., 22
vs 23-38 or 21 vs 46, 47, 54, 56), para substitution
leads to a decrease in D2 binding affinity, but ortho or
meta substitution have no detectable influence (48, 55,
57, and 58).
By application of the GTPγS test, it is confirmed that
the compounds 50 and 54 act as full agonists at the
5-HT1A receptor, though the difference in activity by a
factor of 70 between the ED50 values of these two
derivatives cannot be explained (Table 5). The intrinsic
activity was ascertained in vitro only for these two
compounds in this publication, but we have much
evidence for agonism in the whole structural class as
can be shown by the results in the in vivo inhibition of
ultrasonic vocalization (Table 6).
The fact that the 5-hydroxyindole 1 (roxindole) is
subject to phase II metabolism explains the remarkable
discrepancy in activity after sc and po administration
in Table 6. The oral activity of the ethers 24 and 37 is
still by a factor of 50 and 160 weaker than after sc
application. For the carboxamides 45 and 50, the factor
between sc and po doses is smaller (17 and 21), indicat-
ing that this indole substitution is able to improve oral
bioavailability.
compd
46
R
5-HT1A
D2
4-OHC6H4
0.2 ( 0.2
0.7 ( 0.2
0.1 ( 0.07
0.5 ( 0.2
156 ( 95
47
4-OCH3-3,5-Cl2C6H2
2-OCH3C6H4
>100
1.2 ( 0.3
>100
48
49
50
0.5a ( 0.3
100 ( 52
51
52
2,4-(OCH3)2C6H3 0.07 ( 0.02
0.4 ( 0.2
100 ( 29
22 ( 1.9
53
0.2 ( 0.2
40 ( 17
54
55
56
57
58
59
4-CONH2C6H4 0.9b ( 0.5
>850
97 ( 56
>100
2-CONH2C6H4
4-NHC(O)CH3C6H4
2-CNC6H4
0.3 ( 0.2
0.1 ( 0.1
0.2 ( 0.08
6.2 ( 1.6
5 ( 2.9
2-CN-3-FC6H3 0.01 ( 0.01
0.9 ( 0.6
28 ( 16
a
b
GTPγS, ED50 ) 0.07 nM. GTPγS, ED50 ) 4.7 nM.
Ta ble 6. In Vivo Inhibition of Ultrasonic Vocalization by
Selected Compounds in Rats (ID50 (mg/kg))
serotonin and dopamine receptor subtypes [IC50 (nM)]:
5-HT1D ) 200; 5-HT2A ) 1400; 5-HT2C > 1000; D3 ) 950;
D4 > 1000. Derivative 56 was also tested against
R-adrenergic receptors and showed no relevant affinity
[IC50 (nM)]: 5-HT1D ) 200; 5-HT2C ) 1000; R1 ) 3000;
R2 ) 1000. These results emphasize the selectivity
potential within the discussed scaffold.
1
24
37
39
45
50
sc
po
0.07
16
0.2
10
0.1
16
3
0.1
1.7
0.07
1.5
n.d.a
a
n.d. ) not determined.
In conclusion, it was found that the 3-(piperazinobu-
tyl)indole-5-carboxamide is a very potent 5-HT1A binding
scaffold. When the appropriate arylpiperazine substitu-
ent is chosen, very selective 5-HT1A agonists can be
obtained. The following overview shows the selectivity
profile of a selection of compounds to a series of other
5-HT receptor subtypes and related GPCRs (Table 7).23
To compare the role of the 5-indolyl residue for potent
5-HT1A receptor binding, eight couples of compounds
have to be mentioned explicitly. Within each pair the
phenylpiperazine part is kept constant and the sub-
stituent on the indole is changed (5-methoxy or 5-car-
boxamide respectively). The unsubstituted phenylpip-
erazines 21 and 22 show comparable two-digit-nanomolar
D2 binding, but the carboxamide 21 binds 200 times
better to the 5-HT1A receptor than 22. The phenol 23 is
10-fold less active in 5-HT1A binding as methoxyindole
than as the corresponding carboxamide 46. The intro-
duction of a methyl group improves 5-HT1A binding
affinity of both derivatives equally (24 vs 45), but the
D2 selectivity is better for the carboxamide 45. The
compound pairs 33/49 and 34/50 are selective 5-HT1A
ligands with only weak D2 affinity. In compound pairs
36/52 and 37/53, there are differences between 5-meth-
oxyindole and indolyl-5-carboxamide: The benzodiox-
olecarboxamide 52 binds 20 times better to the 5-HT1A
receptor than the corresponding ether 36 and is 1 order
of magnitude more active at the D2 receptor. The
benzodioxanecarboxamide 53 has comparable 5-HT1A
potential but one power of 10 more D2 affinity than the
ether 37. The acetanilide 56 shows better 5-HT1A
binding as carboxamide than the corresponding methyl
Ta ble 7. Comparison of Selected Compounds in Binding
Affinity to Certain GPCRs (IC50 (nM))
target
24
45
52
ipsapirone
5-HT1A
5-HT1D
5-HT2A
5-HT2C
H1
4
0.09
700
220
n.d.
1000
700
2000
140
0.4
400
240
800
19
100
900
24
8.2
>10000
750
3000
2600
>1000
24
4000
41
1000
7000
420
R1
500
1000
R2
D2
2900a
a
D3 ) 1200. D4 ) 1800. n.d. ) not determined.
Compounds 24 and 52 have some histamine H1
receptor binding affinity that could lead to sedative side
effects in vivo and the affinity of 45 and 52 to the D2
receptor subtype is 140 and 24 nM, respectively.
The combination of typical structural elements of
5-HT agonists (indolealkylamine and phenylpiperazine)

Indolebutylamines as Agonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19 4681
previously prepared ester 16 in 80 mL of 1 N NaOH and 80
mL of dioxane was heated to 80 °C for 2 h. After the mixture
was cooled to room temperature, concentrated HCl was added
to give pH 4 and the precipitate was filtered, washed with
water, acetone, and diethyl ether, and dried to yield 2.0 g (86%)
of 18 as colorless crystals: mp 196-198 °C; 1H NMR (500 MHz,
DMSO-d6) δ 12.34 (br s, 1H), 11.26 (s, 1H), 10.65 (br s, 1H),
8.23 (s, 1H), 7.71 (dd, 1H, J ) 1.2 Hz and J ) 8.5 Hz), 7.41 (d,
1H, J ) 8.5 Hz), 7.33 (m, 2H), 7.29 (s, 1H), 7.24 (m, 3H), 3.51
(m, 2H), 3.34 (m, 3H), 3.01 (m, 2H), 2.99 (m, 2H), 2.79 (m,
3H), 2.10 (m, 2H), 1.93 (m, 2H), 1.83 (m, 2H), 1.71 (m, 2H).
Anal. (C24H28N2O2‚HCl‚H2O) H, N. C: calcd, 66.9; found 65.8.
not only improves 5-HT1A binding affinity but also has
impact on the selectivity to other GPCRs. The described
class of compounds compares well with the structural
elements described previously for arylpiperazines. The
1,1-dioxobenzoisothiazolone of ipsapirone,3 for example,
is replaced by an indole that is preferably substituted
in the 5-position. By suitable substitution of the phenyl
moiety (replacing the pyrimidine moiety in ipsapirone),
selectivity to other GPCRs can be reached. The best
compound in this series is clearly the indolylcarbox-
amide 45. The affinity of compound 45 to the dopa-
minergic receptor subtype 2 is by a factor of more than
1000 weaker than to the serotonergic receptor subtype
1A. For comparison, this ratio (D2/5-HT1A) for ipsapirone
is 300. Furthermore, compound 45 has less histamin-
ergic potential than ipsapirone (by a factor of 40). With
this finding, we were able to provide a new interesting
tool with selectivity and potency for serotonin receptor
research.
Compounds 15, 17, and 19-59 were synthesized according
to the following procedures.
3-{4-[4-(2,3-Dih yd r oben zofu r a n -5-yl)p ip er a zin -1-yl]bu -
t yl}-5-m et h oxy-1H -in d ole (33). A solution of 52.5 g (0.39
mol) of commercially available 2,3-dihydro-1-benzofuran-5-
amine in 300 mL of hot 1-butanol was reacted with 69.6 g (0.34
mol) of bis-(2-chloroethyl)ammonium chloride at 145 °C for 12
h. After addition of 30.4 g (0.22 mol) of potassium carbonate,
the suspension was heated to the given temperature for a
further 12 h. After it was cooled to 80 °C, the precipitating
starting material was filtered, and finally the product was
crystallized at room temperature. The crude material was
recrystallized from ethanol, and an amount of 25.2 g (31%) of
1-(2,3-dihydrobenzfuran-5-yl)piperazine was collected: mp
213-215 °C. Anal. (C12H16N2O‚HCl) C, H, N. Cl: calcd, 14.7;
found, 15.2. To a solution of 4.6 g (20 mmol) of 4-(5-methoxy-
1H-indol-3-yl)butyric acid in 80 mL of THF was added 2.4 mL
(20 mmol) of 2,2-dimethylpropionyl chloride, and the resulting
suspension was stirred for 30 min. Then a solution of 4.8 g
(20 mmol) of the previously prepared 1-(2,3-dihydrobenzfuran-
5-yl)piperazine was added and the solution was stirred for 48
h. For workup, the reaction mixture was concentrated in a
vacuum and the residue was dissolved in 1 N NaOH and ethyl
acetate. After phase separation, the organic precipitate was
filtered and washed with ethyl acetate, yielding 6.1 g (72%) of
1-[4-(2,3-dihydrobenzofuran-5-yl)piperazin-1-yl]-4-(5-methoxy-
1H-indol-3-yl)butan-1-one: mp 149 °C. A suspension of 6.1 g
(15 mmol) of the previously prepared amide in 100 mL of THF
was treated with 10.5 mL (38 mmol) of Vitride (70% in toluene)
and stirred for 2 h at room temperature. After complete
conversion of the starting material, an amount of 8 mL of
water was added at 0 °C, the resulting precipitate was filtered,
and the remaining solution was concentrated in vacuum. The
crude product was recrystallized from ethyl acetate, yielding
2.7 g (45%) of 33 as colorless crystals: mp 110-112 °C; 1H
NMR (300 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.21 (d, 1H, J )
8.7 Hz), 7.05 (d, 1H, J ) 2.2 Hz), 6.96 (d, 1H, J ) 2.4 Hz),
6.86 (d, 1H, J ) 1.3 Hz), 6.69 (dd, 1H, J ) 2.4 Hz and J ) 8.7
Hz), 6.62 (m, 2H), 4.43 (t, 2H, J ) 8.6 Hz), 3.75 (s, 3H), 3.10
(t, 2H, J ) 8.6 Hz), 2.95 (m, 4H), 2.67 (t, 2H, J ) 7.3 Hz), 2.46
(m, 4H), 2.36 (t, 2H, J ) 7.2 Hz), 1.66 (m, 2H), 1.52 (m, 2H).
Anal. (C25H31N3O2) H. C: calcd, 74.0; found, 73.3. N: calcd,
10.3; found, 9.3.
3-[4-(4-Ch r om a n -6-ylp ip er a zin -1-yl)bu tyl]-1H-in d ole-5-
ca r boxa m id e (50). A suspension of 9.3 g (35 mmol) of methyl
3-(4-chlorobutyl)-1H-indole-5-carboxylate,14 10.2 g (35 mmol)
of 1-chroman-6-ylpiperazine,24 14.5 g (0.11 mol) of potassium
carbonate, and 14.6 mL (0.11 mol) of triethylamine in 300 mL
of acetonitrile was heated to reflux for 20 h. After the reaction
mixture had cooled to room temperature, the suspension was
filtered and the filtrate was evaporated to dryness. The
resulting crude material was stirred in ethyl acetate and
water, after phase separation the organic phase was dried and
evaporated, and the resulting oil was purified via chromato-
graphy. The combined and evaporated product fractions were
crystallized from ether/cyclohexane, yielding 5.9 g (37%) of
yellow crystals of methyl 3-[4-(4-chroman-6-ylpiperazin-1-yl)-
butyl]-1H-indole-5-carboxylate: mp 118-121 °C; 1H NMR (300
MHz, DMSO-d6) δ 11.15 (s, 1H), 8.22 (d, 1H, J ) 1.1 Hz), 7.70
(dd, 1H, J ) 1.6 Hz and J ) 8.6 Hz), 7.41 (d, 1H, J ) 8.6 Hz),
7.24 (d, 1H, J ) 2.0 Hz), 6.65 (dd, 1H, J ) 2.7 Hz and J ) 8.9
Hz), 6.59 (m, 2H), 4.03 (φt, 2H), 3.83 (s, 3H), 2.94 (m, 4H),
Exp er im en ta l Section
Melting points were determined on a Bu¨chi 535 melting
1
point apparatus and are uncorrected. IR, H NMR, and mass
spectra are in agreement with the structures and were
recorded on a Bruker IFS 48 IR spectrophotometer, a Bruker
AMX 300 MHz or DRX 500 MHz NMR spectrometer (TMS as
an internal standard), and Vaccum Generators VG 70-70 or
70-250 at 70 eV. Elemental analyses (obtained with a Perkin-
Elmer 240 BCHN analyzer) for the final products were within
0.4% of calculated values if not otherwise stated. All reactions
were followed by TLC carried out on Merck KGaA F254 silica
gel plates. Solutions were dried over Na2SO4 and concentrated
with a Bu¨chi rotary evaporator at low pressure. Phenyl-
piperazines were available from EMKA.
The synthesis of compounds 1 and 10-13 is known from
the literature.14
Gen er a l Meth od for Hyd r ogen a tion : 3-[4-(P h en ylp i-
p er id in -1-yl)bu tyl]-1H-in d ol-5-ol (14). A solution of 4.1 g
(10.7 mmol) of 3-[4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-
butyl-1H-indol-5-ol hydrochloride in 30 mL of methanol was
reacted with 0.56 L of hydrogen (normal pressure) with a 5%
Pd/charcoal contact (1.4 g) for 120 min at 40 °C and filtered
hot after complete conversion. The precipitate was recrystal-
lized from methanol, yielding 2.6 g (63%) of 14: mp 228-230
°C; 1H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.41 (br s,
1H), 8.58 (s, 1H), 7.33 (t, 2H, J ) 7.1 Hz), 7.23 (d, 3H, J ) 7.1
Hz), 7.12 (d, 1H, J ) 8.6 Hz), 7.04 (s, 1H), 6.82 (s, 1H), 6.60
(dd, 1H, J ) 2.2 Hz and J ) 8.6 Hz), 3.51 (d, 2H, J ) 11.8
Hz), 3.07 (m, 2H), 2.98 (m, 2H), 2.80 (m, 1H), 2.64 (t, 2H, J )
7.1 Hz), 2.06 (m, 2H), 1.93 (m, 2H), 1.79 (m, 2H), 1.66 (m, 2H).
Anal. (C23H28N2O‚HCl) C, H, N, Cl.
Gen er a l Meth od for Cou p lin g of a n In d olebu tyl Moie-
ty w ith P h en ylp ip er id in e or P h en ylp ip er a zin e: Meth yl
3-[4-(4-P h en ylp ip er id in -1-yl)bu tyl]-1H-in d ole-5-ca r boxy-
la te (16). A solution of 65 g (0.2 mol) of methyl 3-(4-
methanesulfonyloxybutyl)-1H-indole-5-carboxylate,14 19.7 g
(0.1 mol) of 4-phenylpiperidine hydrochloride, and 55.4 mL of
triethylamine in 500 mL of methanol was refluxed for 7 h.
After complete conversion of the piperidine ingredient, the
solvent was removed and the crude product was dissolved in
acetone. After the addition of HCl-saturated ethanol to pH 4
the precipitate was filtered and washed with acetone and
diethyl ether, yielding 6.1 g (14%) of 16 as colorless crystals:
mp 204-206 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.30 (s,
1H), 10.50 (br s, 1H), 8.23 (s, 1H), 7.72 (dd, 1H, J ) 1.5 Hz
and J ) 8.5 Hz), 7.43 (d, 1H, J ) 8.5 Hz), 7.33 (m, 3H), 7.23
(m, 3H), 3.85 (s, 3H), 3.52 (d, 2H, J ) 11.0 Hz), 3.10 (m, 2H),
2.99 (q, 2H, J ) 11.0 Hz), 2.79 (t, 3H, J ) 7.7 Hz), 2.09 (m,
2H), 1.94 (m, 2H), 1.83 (m, 2H), 1.71 (m, 2H). Anal. (C25H30N2O2‚
HCl) C, H, N.
3-[4-(4-P h en ylp ip er id in -1-yl)b u t yl]-1H -in d ole-5-ca r -
boxylic Acid (18). A solution of 2.4 g (5.6 mmol) of the

4682 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19
Heinrich et al.
2.75 (t, 2H, J ) 6.6 Hz), 2.68 (t, 2H, J ) 6.4 Hz), 2.45 (m, 4H),
2.34 (t, 2H J ) 6.6 Hz), 1.87 (m, 2H), 1.69 (m, 2H), 1.52 (m,
2H). Anal. (C27H33N3O3) C, H, N. A solution of 5.5 g (13 mmol)
of the previously prepared methyl ester in 50 mL of dioxane
was heated with 52 mL (52 mmol) of 1 N NaOH to 80 °C for
2 h. After the solution had cooled to room temperature
concentrated HCl was added, leading to precipitation. Pre-
cipitation was completed at 7 °C for 12 h, and after filtration
and drying 5.8 g (98%) of fawn crystals of 3-[4-(4-chroman-6-
ylpiperazin-1-yl)butyl]-1H-indole-5-carboxylic acid hydrochlo-
ride were collected: mp 245-247 °C; 1H NMR (300 MHz,
DMSO-d6) δ 12.30 (br s, 1H), 11.18 (s, 1H), 10.55 (br s, 1H),
8.20 (s, 1H), 7.69 (dd, 1H, J ) 1.5 Hz and J ) 8.5 Hz), 7.38 (d,
1H, J ) 8.5 Hz), 7.26 (d, 1H, J ) 1.8 Hz), 6.72 (dd, 1H, J )
2.8 Hz and J ) 8.8 Hz), 6.63 (m, 2H), 4.04 (φt, 2H), 3.29 (m,
4H), 3.06 (m, 4H), 2.77 (t, 2H, J ) 6.5 Hz), 2.69 (t, 4H, J ) 6.4
Hz), 1.87 (m, 2H), 1.71 (m, 4H). Anal. (C25H29N3O3‚HCl) H,
Cl. C: calcd, 65.9; found, 64.8. N: calcd, 9.2; found, 9.9. A
solution of 5.6 g (11 mmol) of the previously prepared acid and
5.6 g (22 mmol) of 1-methyl-2-chloropyridinium iodide (CMPJ )
in 50 mL of 1-methylpyrrolidin-2-one (NMP) was stirred at
room temperature, and 7.3 mL (44 mmol) of N,N-diisopropyl-
ethylamine (DIPEA) were added drop by drop before NH3 gas
was introduced for 2 h. The mixture reached 63 °C and cooled
to room temperature after completion. Then 50 mL of 1 N
NaOH and 100 mL of water were added. The precipitate (4.4
g) was collected and recrystallized from 100 mL of ethanol,
yielding 2.6 g (55%) 50: mp 177-179 °C; 1H NMR (500 MHz,
DMSO-d6) δ 10.95 (br s, 1H), 8.15 (s, 1H), 7.80 (br s, 1H), 7.64
(dd, 1H, J ) 1.6 Hz and J ) 8.5 Hz), 7.32 (d, 1H, J ) 8.5 Hz),
7.17 (d, 1H, J ) 2.2 Hz), 7.02 (br s, 1H), 6.66 (dd, 1H, J ) 2.8
Hz and J ) 8.8 Hz), 6.58 (s, 1H), 6.57 (d, 1H, J ) 8.8 Hz), 4.03
(t, 2H, J ) 5.1 Hz), 2.94 (t, 4H, J ) 4.7 Hz), 2.74 (t, 2H, J )
7.5 Hz), 2.68 (t, 2H, J ) 6.5 Hz), 2.45 (t, 4H, J ) 4.8 Hz), 2.35
(t, 2H, J ) 7.4 Hz), 1.86 (m, 2H), 1.69 (m, 2H), 1.53 (m, 2H).
Anal. (C26H34N4O2) C, H, N.
terminated by rapid filtration (Whatman GF/B) and three
washes with ice-cold buffer. Nonspecific binding was deter-
mined in the presence of 1 mmol/L (+)-butaclamol.17
R a d ioliga n d Bin d in g Assa y a t R a t H ip p oca m p u s
5-HT1A Ser oton er gic Recep tor s. The method was adapted
from Cossery et al.26 Rat hippocampus membranes (0.2 mg
protein/tube) were incubated with 0.5 nM [3H]-8-OH-DPAT in
a total volume of 0.5 mL at 25 °C for 30 min. Nonspecific
binding was determined in the presence of 1 µM serotonin.
Stim u la tion of [35S]GTP γS bin d in g a t Clon ed 5-HT1A
Recep tor s. The effects of different compounds tested on [35S]-
GTPγS binding were evaluated according to a method of
Newman-Tancredi et al.19 with modifications. Membranes of
CHO cells stably expressing the recombinant human 5-HT1A
receptor were obtained from NEN (catalog no. CRM035,
GenBank no. X13556). The membranes were stored at -70
°C. Prior to use, membranes were thawed and rehomogenized
in assay buffer (MgCl2, NaCl, and EDTA in Tris-HCl, pH 7.4).
Membranes (∼10 µg of protein) were incubated at 37 °C for
30 min (shaking water bath) in duplicate in a total volume of
800 µL of buffer containing MgCl2 (3 mM), NaCl (120 mM),
EDTA (0.2 mM), GDP (10 µM), [35S]GTPγS (0.1 nM), Tris (50
mM), and test compounds. Prior to addition to the incubation
mixture, the test compounds were dissolved in twice distilled
water. DMSO was used to aid in solubilizing certain com-
pounds. Nonspecific binding was defined with 0.1 µM GTPγS.
5-HT was tested as standard in each experiment at concentra-
tions of 100, 30, and 10 nM. Experiments were terminated by
rapid filtration through Whatman GF/B filters using a Brandel
cell harvester. Subsequently, the filters were rinsed twice with
5 mL of ice-cold Tris-HCl and placed in scintillation vials.
Radioactivity was extracted in 4 mL of scintillation fluid
(Ultima Gold, Packard Instruments, Frankfurt, Germany) and
determined by liquid scintillation counting. Binding isotherms
were analyzed by nonlinear regression. Agonist efficacy ()Emax
)
is expressed relative to that of 5-HT ()100%), which was tested
at a maximally active concentration (0.1 mM) in each experi-
ment. EC50 values were defined as the concentration of the
compound at which 50% of its own maximal stimulation was
obtained.
3-{4-[4-(4-Ca r ba m oylp h en yl)p ip er a zin -1-yl]bu tyl}-1H-
in d ole-5-ca r boxa m id e (54). A suspension of 5 g (19 mmol)
of methyl 3-(4-chloro-butyl)-1H-indole-5-carboxylate,14 4.6 g (12
mmol) of 4-piperazin-1-ylbenzamide,25 5.2 g (38 mmol) of
potassium carbonate, and 5 mL (38 mmol) of triethylamine in
200 mL of acetonitrile was coupled as described above, yielding
1.7 g (20%) of methyl 3-{4-[4-(carbamoylphenyl)piperazin-1-
yl]butyl}-1H-indole-5-carboxylate. Without further purification
the ester (1.7 g, 4 mmol) was hydrolyzed with 1 N NaOH (12
mL) as described above, yielding 1.2 g (67%) of 3-{4-[4-
(carbamoylphenyl)piperazin-1-yl]butyl}-1H-indole-5-carboxy-
lic acid hydrochloride as colorless crystals: mp 288-290 °C;
1H NMR (300 MHz, DMSO-d6) δ 12.31 (br s, 1H), 11.14 (s,
1H), 9.76 (br s, 1H), 8.19 (s, 1H), 7.77 (d, 2H, J ) 8.8 Hz), 7.68
(dd, 2H, J ) 1.8 Hz, J ) 8.6 Hz), 7.38 (d, 1H J ) 8.6 Hz), 7.25
(d, 1H, J ) 1.8 Hz), 7.00 (br m, 3H), 3.95 (m, 2H), 3.54 (m,
2H), 3.19 (m, 2H), 3.08 (m, 4H), 2.77 (m, 2H), 1.71 (m, 4H).
Anal. (C24H28N4O3‚HCl) H, Cl. C: calcd, 63.1; found, 61.2. N:
calcd, 12.3; found, 11.8. The previously prepared acid (1.1 g,
2.4 mmol), 1.5 g (6 mmol) of CMPJ , and 1.7 mL (9 mmol) of
DIPEA in 30 mL of NMP were reacted as described above,
giving 0.9 g (90%) of the corresponding carboxamide semihy-
drate 54 as colorless crystals: mp 138-140 °C; 1H NMR (500
MHz, DMSO-d6) δ 10.89 (d, 1H, J ) 2.2 Hz), 8.19 (d, 1H, J )
1.7 Hz), 7.86 (br s, 2H), 7.76 (d, 2H, J ) 8.9 Hz), 7.67 (dd, 1H,
J ) 1.7 Hz and J ) 8.5 Hz), 7.36 (d, 1H, J ) 8.5 Hz), 7.21 (d,
1H, J ) 2.3 Hz), 7.04 (br s, 2H), 6.93 (d, 1H, J ) 8.9 Hz), 3.24
(m, 4H), 2.77 (t, 2H, J ) 7.0 Hz), 2.48 (m, 4H), 2.38 (t, 2H, J
) 7.0 Hz), 1.77-1.56 (m, 4H). Anal. (C24H29N5O2‚0.5 H2O) C,
H, N.
Ultr a son ic Voca liza tion Test. Male rats weighing 180-
280 g from Charles River (Sulzfeld, Germany) were used.
Ultrasonic vocalization was measured in a sound-attenuated
test chamber (W 24 cm, L 22 cm, H 22 cm) with a grid floor
for delivery of foot shock (scrambled shock of 0.2 mA for 0.5 s,
shocker Getra BN 2002). Ultrasonic vocalization was recorded
(microphone 4004, Bruel and Kjær) and processed by an
interface (developed at Merck KGaA, Darmstadt) to select 22
( 4 kHz signals and to digitize the resulting signals for
automatic processing in a personal computer. In a priming
phase, each rat was placed in the test chamber. After a 2 min
time period, a series of at most 10 shocks (trials), 1.8 mA for
0.3 s, separated by 20 s shock-free intervals, was delivered
via the grid floor of the test chamber. In the shock-free
intervals the occurrence of ultrasonic vocalization was auto-
matically recorded, and the duration of ultrasonic vocalization
was calculated immediately. The priming session was termi-
nated either when the rat constantly vocalized at least for 10
s on three consecutive trials or after the tenth trial. Rats that
did not respond with ultrasonic vocalization on three consecu-
tive trials were excluded from further testing. In the actual
test performed on the next day, each rat received five initial
shocks (1.8 mA for 0.3 s, separated by 20 s shock-free intervals)
in the test chamber, and the duration of ultrasonic vocalization
was recorded during the following 3 min period. Animals were
tested 2 h after administration of compounds. ID50 values
()calculated dose for half-maximal inhibition of ultrasonic
vocalization) were determined from the dose-response curves.
P h a r m a cologica l Meth od s. Recep tor Bin d in g Assa ys.
The affinity of compounds for dopamine receptors were
determined in a total volume of 2 mL containing 0.1 nM [3H]-
spiperone and 0.3-1.0 mg of protein of rat striatal membranes
per milliliter. Assay buffer was 50 mol/L Tris-HCl, pH 7.1, 120
mmol/L NaCl, 5 mmol/L KCl, 1 mmol/L CaCl2, 1 mmol/L
MgCl2, 50 mmol Tris/HCl, pH 7.7, and 0.1% ascorbic acid.
Incubations were carried out at 37 °C for 15 min and
Ack n ow led gm en t. We thank Horst Hochsta¨tter,
Marion Sturm, Claudia Daum, Bernd Arzt, Beate Opelt,
Andreas J onke, Uwe Eckert, and Kurt Schuster for the
preparation of the compounds and Herbert Ziegler for
performing pharmacological tests.

Indolebutylamines as Agonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 19 4683
Exp. Ther. 2002, 303, 791-804. (b) Newman-Tancredi, A.;
Cussac, D.; Quentric, Y.; Touzard, M.; Verrie`le, L.; Carpentier,
N.; Millan, M. J . Differential Actions of Antiparkinson Agents
at Multiple Classes of Monoaminergic Receptor. III. Agonist and
Antagonist Properties at Serotonin, 5-HT1 and 5-HT2, Receptor
Subtypes. J . Pharmacol. Exp. Ther. 2002, 303, 815-822. (c)
Newman-Tancredi, A.; Cussac, D.; Audinot, V.; Nicolas, J . P.;
De Ceuninck, F.; Boutin, J . A.; Millan, M. J . Differential Actions
of Antiparkinson Agents at Multiple Classes of Monoaminergic
Receptor. II. Agonist and Antagonist Properties at Subtypes of
Dopamine D2-Like Receptor and R1/R2-Adrenoceptor. J . Phar-
macol. Exp. Ther. 2002, 303, 805-814.
Su p p or tin g In for m a tion Ava ila ble: Spectral data, el-
emental analyses, and melting points for compounds 1 and
10-59. This material is available free of charge via the
Internet at http://pubs.acs.org.
Refer en ces
(1) (a) Mellin, C.; Vallgarda, J .; Nelson, D. L.; Bjo¨rk, L.; Yu, H.;
Ande´n, N.-E.; Cso¨regh, I.; Arvidsson, L. E.; Hacksell, U. A
3-Dimensional Model for 5-HT1A-Receptor Agonists Based on
Stereoselective Methyl-Substituted and Conformationally Re-
stricted Analogues of 8-Hydroxy-2-(dipropylamino)tetralin. J .
Med. Chem. 1991, 34, 497-510 and ref 4 cited therein. (b) Clark,
R. D.; Weinhardt, K. K.; Berger, J .; Fisher, L. E.; Brown, C. M.;
MacKinnon, A. C.; Kilpatrick, A. T.; Spedding, M. 1,9-Alkano-
Bridged 2,3,4,5-Tetrahydro-1H-3-Benzazepines with Affinity for
the R2-Adrenoceptor and the 5-HT1A Receptor. J . Med. Chem.
1990, 33, 633-641.
(2) (a) Rasmussen, K.; Rocco, V. P. Recent Progress in Serotonin
(5-HT)1A Receptor Modulators. Annu. Rep. Med. Chem. 1995,
30, 1-9. (b) Romero, A. G.; McCall, R. B. Advances in Central
Serotoninergics. Annu. Rep. Med. Chem. 1992, 27, 21-30.
(3) (a) Traber, J .; Davies, M. A.; Dompert, M. U.; Glaser, T.;
Schuurman, T.; Seidel, P. R. Brain Serotonin Receptors as a
Target for the Putative Anxiolytic TVX Q 7821. Brain Res. Bull.
1984, 12, 741-744. (b) Fanelli, A. J .; Schuurman, T.; Glaser,
T.; Traber, J . Ipsapirone: A Novel Anxiolytic and Selective
5-HT1A Receptor Ligand. Prog. Clin. Biol. Res. 1990, 361, 461-
467. (c) Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.;
Tortorella, V.; Fornaretto, M. G.; Caccia, C.; McArthur, R. A.
Structure-Activity Relationship Studies on the 5-HT1A Receptor
Affinity of 1-Phenyl-4-[ω-(R- or â-tetralinyl)alkyl]piperazines. J .
Med. Chem. 1996, 39, 4928-4934.
(4) Van Wijngaarden, I.; Soundijn, W.; Tulp, M. Th. M. 5-HT1A
Receptor Ligands. Pharmacochem. Libr. 1997, 27, 17-43 and
refs 1-5 cited therein.
(5) (a) Van Wijngaarden, I.; Tulp, M. Th. M.; Soundijn, W. The
Concept of Selectivity in 5-HT Receptor Research. Eur. J .
Pharmacol., Mol. Pharmacol. Sect. 1990, 188, 301-312. (b)
Bartoszyk, G. D.; Bo¨ttcher, H.; Greiner, H.; Harting, J .; Seyfried,
C. A. Pharmacological Profile of the 5-HT1A-Anxiolytic EMD
56551. Presented at the Society of Neuroscience, New Orleans,
LA, 1991; Abstract 637.8.
(6) (a) Bo¨ss, F. G.; Martin, I. L. Molecular Biology of 5-HT Receptors.
Neuropharmacology 1994, 33, 275-317. (b) Hibert, M. F.;
McDermott, I.; Middlemiss, D. N.; Mir, A. K. Radioligand
Binding Study of a Series of 5-HT1A Receptor Agonists and
Definition of a Steric Model of this Side. Eur. J . Med. Chem.
1989, 24, 31-37. (c) Hoyer, D.; Scho¨ffert, P. 5-HT Receptors:
Subtypes and Second Messengers. J . Recept. Res. 1991, 11, 197-
214.
(7) (a) Seyfried, C. A.; Fuxe, K.; Wolf, H.-P.; Agnati, L. F. Demon-
stration of a New Type of Dopamine Receptor Agonist: An
Indole-3-Butyl Amine. Actions at Intact Versus Supersensitive
Dopamine Receptors in the Rat Forebrain. Acta Physiol. Scand.
1982, 116, 465-468. (b) Hausberg, H.-H.; Bo¨ttcher, H.; Fuchs,
A.; Gottschlich, R.; Koppe, V.; Minck, K.-O.; Poetsch, E.; Saiko,
O.; Seyfried, C. A. Indole-Alkyl-Piperidines, a New Class of
Dopamine Agonists. Acta Pharm. Suec. (Suppl.) 1983, 2, 213-
217. (c) Bartoszyk, G. D.; Harting, J .; Minck, K.-O. Roxindole:
Psychopharmacological Profile of a Dopamine D2 Autoreceptor
Agonist. J . Pharmacol. Exp. Ther. 1996, 276, 41-48. (d) Seyfried,
C. A.; Greiner, H. E.; Haase, A. F. Biochemical and Functional
Studies on EMD 49980: A Potent, Selectively Presynaptic D2
Dopamine Agonist with Actions on Serotonin Systems. Eur. J .
Pharmacol. 1998, 160, 31-41.
(10) Bu¨hring, K. U. Unpublished results for discussion: Karl-
Ulrich.Buehring@merck.de.
(11) Schmidle, C. J .; Mansfield, R. C. The Aminomethylation of
Olefins. V. A New Synthesis of 4-Phenylpyridine and Related
Compounds. J . Am. Chem. Soc. 1956, 78, 1702-1705.
(12) Egawa, H.; Kataoka, M.; Shibamori, K.-I.; Miyamoto, T.; Nakano,
J.; Matsumoto, J.-i. Pyridonecarboxylic Acid Antibacterial Agents.
Part 7. A New Synthetic Route to 7-Halo-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxoquinolines-3-carboxylic Acid, an Intermediate
for the Synthesis of Quinolone Antibacterial Agents. J . Hetero-
cycl. Chem. 1987, 24, 181-185.
(13) Prelog, V.; Driza, G. J . Bis(â-haloethyl)amines III. N-Phenyl-
Piperazines. Collect. Czech. Chem. Commun. 1933, 5, 497-502.
(14) Bo¨ttcher, H.; Gericke, R. Synthese von 3-[4-(1,2,3,6-Tetrahydro-
4-phenyl-1-pyridyl)butyl]-5-indolcarbonsa¨ure, eine blutrucksen-
kende Verbindung mit neuartigem Wirkprinzip. Liebigs Ann.
Chem. 1988, 749-752.
(15) Mukaiyama, T. New Synthetic Methods. 29. New Syntheses with
Onium Salts of Azaarenes. Angew. Chem. 1979, 91, 798-812
(IE 1979, 18, 707-721).
(16) Clack, D. W.; J ackson, A. H.; Prasitpan, N.; Shannon, P. V. R.
Electrophilic Substitution in Indoles. Part 11. The Mechanism
of Substitution in 5-Methoxyindoles. J . Chem. Soc., Perkin
Trans. 2 1982, 909-916.
(17) Matzen, L.; van Amsterdam, C.; Rautenberg, W.; Greiner, H.
E.; Harting, J .; Seyfried, C. A.; Bo¨ttcher, H. 5-HT Reuptake
Inhibitors with 5-HT1B/1D Antagonistic Activity: A New Ap-
proach toward Efficient Antidepressants. J . Med. Chem. 2000,
43, 1149-1157.
(18) Urwyler, S.; Markstein, R. Identification of Dopamine D3 and
D4 Binding Sites Labled with [3H] 2-Amino-6,7-dihydroxy-
1,2,3,4-tetrahydronaphthalene as High Agonist Affinity States
of the D1 and D2 Dopamine Receptors, respectively. J . Neuro-
chem. 1986, 46, 1058-1067.
(19) Newman-Tancredi, A.; Chaput, C.; Verrie`le, L.; Millan, M. J .
S15535 and WAY100,635 Antagonize 5-HT-Stimulated [35S]
GTPγS Binding at Cloned Human 5-HT1A Receptors. Eur. J .
Pharmacol. 1996, 307, 107-111.
(20) De Vry, J .; Benz, U.; Schreiber, R.; Traber, J . Shock-Induced
Ultrasonic Vocalization in Young Adult Rats: A Model for
Testing Putative Anti-Anxiety Drugs. Eur. J . Pharmacol. 1993,
249, 331-339.
(21) Oh, S. J .; Ha, H.-J .; Chi, D. Y.; Lee, H. K. Serotonin Receptor
and Transporter LigandssCurrent Status. Curr. Med. Chem.
2001, 8, 999-1034.
(22) Haase, A. F.; Greiner, H. E.; Seyfried, C. A. Neurochemical
profile of EMD 45609 (carmoxirole), a dopamine DA2-receptor
agonist. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1991, 343,
588-594.
(23) Trumpp-Kallmeyer, S.; Hoflack, J .; Bruinvels, A.; Hilbert, H.
Modeling of G-Protein-Coupled Receptors: Application to Dopam-
ine, Adrenaline, Serotonin, Acetylcholine, and Mammalian Opsin
Receptors. J . Med. Chem. 1992, 35, 3448-3462.
(24) Ward, Y. D.; Farina, V. Solid Phase Synthesis of Aryl Amines
via Palladium Catalyzed Amination of Resin-Bound Aromatic
Bromides. Tetrahedron Lett. 1996, 37, 6993-6996.
(25) Hodgetts, K. J .; Kieltyka, A.; Brodbeck, R.; Tran, J . N.; Wasley,
J . W. F.; Thurkauf, A. 6-(4-Benzylpiperazin-1-yl)benzodioxanes
as Selective Ligands at Cloned Primate Dopamine D4 Receptors.
Bioorg. Med. Chem. 2001, 9, 3207-3214.
(26) Cossery, J . M.; Gozlan, H.; Spampinato, U.; Perdicakis, C.;
Guillaumet, G.; Pichat, L.; Hamon, M. The Selective Labelling
of Central 5-HT1A Receptor Binding Sites by [3H]5-Methoxy-3-
(di-n-propylamino)-chroman. Eur. J . Pharmacol. 1987, 140,
143-155.
(8) (a) Bo¨ttcher, H.; Barnickel, G.; Hausberg, H.-H.; Haase, A. F.;
Seyfried, C. A.; Eiermann, V. Synthesis and Dopaminergic
Activity of Some 3-(1,2,3,6-tetrahydro-1-pyridylalkyl)indoles. A
Novel Conformational Model To Explain Structure-Activity
Relationships. J . Med. Chem. 1992, 35, 4020-4026. (b) Lange,
J . H. M.; de J ong, J . C.; Sanders, H. J .; Visser, G. M.; Kruse, C.
G. A Straightforward Synthetic Approach for Roxindole. Bioorg.
Med. Chem. Lett. 1999, 9, 1055-1056.
(9) (a) Millan, M. J .; Maiofiss, L.; Cussac, D.; Audinot, V.; Boutin,
J .-A.; Newman-Tancredi, A. Differential Actions of Antiparkin-
son Agents at Multiple Classes of Monoaminergic Receptors. I.
A Multivariate Analysis of the Binding Profiles of 14 Drugs at
21 Native and Cloned Human Receptor Subtypes. J . Pharmacol.
J M040792Y