Synthesis of 2-(5-Bromo-2,3-dimethoxyphenyl)-5-(aminomethyl)-1H-pyrrole analogues and their binding affinities for dopamine D2, D3, and D4 receptors

Article abstract of DOI:10.1016/S0968-0896(02)00341-3

A series of 2-(5-bromo-2,3-dimethoxyphenyl)-5-(aminomethyl)-1H-pyrrole analogues was prepared and their affinity for dopamine D₂, D₃, and D₄ receptors was measured using in vitro binding assays. The results of receptor bin

Full text of DOI:10.1016/S0968-0896(02)00341-3

Bioorganic & Medicinal Chemistry 11 (2003) 225–233
Synthesis of 2-(5-Bromo-2,3-dimethoxyphenyl)-5-(aminomethyl)-
1H-pyrrole Analogues and Their Binding Affinities for Dopamine
D2, D3, and D4 Receptors
Robert H. Mach,a,b,* Yunsheng Huang,a Rebekah A. Freeman,c Li Wu,a Suwanna Blaira
and Robert R. Luedtkec
aDepartment of Radiology, PET Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
bDepartment of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
cDepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
Received 22 March 2002; accepted 19 July 2002
Abstract—A series of 2-(5-bromo-2,3-dimethoxyphenyl)-5-(aminomethyl)-1H-pyrrole analogues was prepared and their affinity for
dopamine D2, D3, and D4 receptors was measured using in vitro binding assays. The results of receptor binding studies indicated
that the incorporation of a pyrrole moiety between the phenyl ring and the basic nitrogen resulted in a significant increase in the
selectivity for dopamine D3 receptors. The most selective compound in this series is 2-(5-bromo-2,3-dimethoxyphenyl)-5-(2-(3-pyr-
idal)piperidinyl)methyl-1H-pyrrole (6p), which has a D3 receptor affinity of 4.3 nM, a 20-fold selectivity for D3 versus D2 receptors,
and a 300-fold selectivity for D3 versus D4 receptors. This compound is predicted to be a useful ligand for studying the functional
role of dopamine D3 receptors in vivo.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
The clinical effects of antipsychotics are thought to be
due to their action on the D2-like receptors in the
mesolimbic system, whereas the extrapyramidal side
effects are thought to result after chronic blockade of
D2-like receptors in the striatrum.1,3 The localization of
D3 receptors in the limbic regions of brain suggest that
this receptor subtype may be a target for the develop-
ment of antipsychotics, with a reduced risk of causing
extrapyramidal side effects.1,4À6 This hypothesis is
supported by the observation that most typical anti-
psychotics display a higher affinity for D2 versus D3
receptors and have a tendency to produce extra-
pyramidal symptoms.1,5 In contrast, atypical anti-
psychotics have a high affinity for both D2 and D3
receptors and a low risk of antipsychotic side effects.5,6
Therefore, a dopamine antagonist that binds with high
affinity at D3 receptors and a lower affinity at D2
receptors is predicted to be a useful antipsychotic with a
decreased probability of causing extrapyramidal side
effects. A number of recent studies have also indicated
that D3 receptor stimulation may mediate the reinforcing
effects of cocaine.7À10 Therefore, D3 receptor antagonists
may be useful for the treatment of cocaine abuse.8À10
Mulitple neurological and neuropsychiatric disorders,
including Parkinson’s disease. Tourette’s syndrome,
tardive dyskinesia, schizophrenia, schizoaffective disorders
and addiction to psychostimulants, have been linked to an
alteration in the function of the dopaminergic system.1À3
There are two major pharmacologic classes of receptors
that mediate dopaminergic neurotransmission, dopamine
D1-like (D1, D5) and D2-like (D2, D3, and D4)
receptors.1À3 Agonist stimulation of the D1-like receptors
causes an increase in adenylyl cyclase activity and a
stimulation of K+ efflux.2 Agonist activation of the
D2-like receptors results in an inhibition of adenylyl
cyclase activity, an increase in the release of arachadonic
acid, and an increase in phosphatidylinositol hydrolysis.2
A complete understanding of the pharmacological and
physiological roles of the different subtypes of the D1-like
and D2-like receptors has been hindered by a lack of
compounds with selectivity for each individual dopamine
subtype.
*Corresponding author. E-mail: rhmach@mir.wustl.edu
0968-0896/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00341-3

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R. H. Mach et al. / Bioorg. Med. Chem. 11 (2003) 225–233
Recently, we reported a number of naphthamide analogues
that bind with high affinity at dopamine D3 receptors with
a reduced affinity for D2 receptors.11 Unfortunately, the
majority of these compounds also possessed a high affinity
for sigma receptors, limiting their utility as dopamine
D3 receptor probes. In a subsequent study, we reported
the synthesis and in vitro binding of a number of imi-
dazole analogues having a modest D3 receptor affinity
and a reduced affinity for dopamine D2 receptors.12
These compounds possessed a low affinity for sigma
receptors, indicating that they may be useful agents for
studying the function of dopamine D3 receptors in vivo.
For example, compound 1c (Fig. 1) has a 4-fold higher
affinity for D3 versus D2 receptors and a negligible affinity
for s1 and s2 receptors (Table 1).
Results
Chemistry
The synthesis of 2-(2,3-dimethoxyphenyl)-1H-pyrrole
and 2-(5-bromo-2,3-dimethoxyphenyl)-1H-pyrrole was
accomplished via the sequence of reactions outlined in
Scheme 1. Mannich reaction with the appropriate
secondary amine gave the final product in moderate to
high yield. The corresponding 2-(2-(4-bromo-1-methoxy-
naphthyl)-1H-pyrrole analogues were synthesized in a
similar manner as outlined in Scheme 2.
Receptor binding
The in vitro receptor binding results are shown in
Tables 1 and 2. The binding affinity of compounds 5a
was 44.6 nM for D2 receptors, and 99.4 nM for D3
receptors. Compound 6a, which contains a 5-bromo
substitution on the benzamide aromatic ring, displayed a
modest in affinity for D2 receptors and a 26-fold increase
in affinity for dopamine D3 receptors in comparison with
the binding data of compound 5a. These results are con-
sistent with our previous study on structurally-related
imidazole analogues.12 Addition of a 6,7-dimethoxy
group in the 1,2,3,4-tetrahydroisoquinoline moiety of 6a
(i.e., 6b) did not alter the affinity for D2 and D3 receptors.
However, this substitution resulted in a 2.5-fold reduction
in affinity for dopamine D4 receptors (Table 2). Fur-
thermore, a comparison of the in vitro binding affinity
of 6b versus that of 1b (Table 2) indicated that sub-
stitution of the imidazole ring with a pyrrole results in
an improvement in affinity for D2 and D3 receptors and
an increase in D3 selectivity. Substitution of the 1-position
of the 1,2,3,4-tetrahydroisoquinoline moiety of 6b with
a methyl group had no effect on D2 receptor affinity but
resulted in a 6-fold reduction in D3 affinity. This is in
Previous studies have shown that replacing the benza-
mide moiety of sultopride with a pyrrole ring (i.e., DU
122290; Fig. 1) resulted in an improvement in the D3
selectivity of this class of compounds.13 This study lead
to the identification of a number of pyrrole analogues
possessing a modest affinity and selectivity for D3 versus
D2 receptors.14,15 The goal of the current study was to
replace the imidazole moiety of compounds such as 1
with a pyrrole ring in order to determine the effect of
this structural change on D3, D2, s1, and s2 receptor
affinity. In addition, in vitro binding assays were con-
ducted on a number of D3-selective compounds in order
to determine their affinity for dopamine D4 receptors. The
results of this study revealed a number of compounds
having a high affinity for dopamine D3 receptors versus
D2 and D4 receptors. All compounds tested had low
affinity for s1 and s2 receptors. Several of the compounds
reported below are expected to be useful probes in
studying the functional role of dopamine D3 receptors
in vivo.
Figure 1.

R. H. Mach et al. / Bioorg. Med. Chem. 11 (2003) 225–233
227
Table 1. Binding affinities for dopamine D2/D3 and sigma s1/s2
receptors
nanomolar affinity for D3 receptor and a 10-fold selec-
tivity for D3 versus D2 receptors and a 20-fold
selectivity for D3 versus D4 receptors (Table 2). Addition
of a phenyl group to give the corresponding dibenzyl
analogue, 6h, resulted in a complete loss in affinity for
both D2 and D3 receptors.
Compd
Ki (nM)a
b
c
d
e
D2
D3
s1
s2
5a
6a
6b
6c
6d
6e
44.6Æ11.8
29.5Æ1.5
99.4Æ19.8
3.8Æ1.2
ND
ND
>1000
>1000
>1000
>1000
>1000
>1000
275Æ22
136Æ8
166Æ31
167Æ14
112Æ4
>1000
>1000
>1000
>1000
>1000
390Æ38
>1000
>1000
>1000
>1000
309Æ6
>1000
>1000
>1000
542Æ19
>1000
>1000
460Æ27
500Æ11
52Æ5
The piperidinylmethyl analogue, 6i, also had a high
affinity for dopamine D3 receptors and a D3/D2 selec-
tivity ratio and a D3/D4 selectivity ratio of ꢀ10 (Table
2). Compounds 6j, 6k, 6l, and 6p demonstrate the effect
of an aromatic ring in the piperidine ring of 6i. Sub-
stitution of either the 2- or 4-position of the piperidine
ring resulted in either no change or a modest reduction
in affinity for dopamine D2 and D3 receptors. However,
this substitution resulted in a pronounced reduction in
affinity for dopamine D4 receptors. For example, com-
pounds 6l and 6p had a low affinity for dopamine D4
receptors, whereas compound 6i had a D4 affinity of
18.4 nM (Table 2).
33.4Æ6.0
3.9Æ0.5
26.3Æ4.8
23.8Æ7.3
8.6Æ3.0
26.2Æ12.8
373.0Æ40.0
51.2Æ12.0
6.6Æ0.6
1560Æ165
12.0Æ6.7
0.6Æ0.2
>1000
>1000
704Æ21
286Æ11
512Æ10
219Æ36
352Æ7
>1000
>1000
>1000
>1000
>1000
307Æ12
>1000
26Æ2
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
11a
11b
11c
11d
1a
1b
1c
13,920Æ3150
19.0Æ2.6
5425Æ1630
1.9Æ0.6
10.9Æ4.1
5.4Æ3.8
22.3Æ3.0
14.1Æ0.9
2.6Æ21.4
98.4Æ23.7
21.0Æ10.7
14.5Æ5.7
4.3Æ2.5
27.8Æ11.0
135.6Æ1.9
31.5Æ6.7
34.4Æ5.8
86.8Æ7.3
17.4Æ1.2
1.7Æ0.6
169.1Æ15.1
303.0Æ52.0
253.6Æ54.2
354.2Æ41.4
198.7Æ137.0
315.5Æ140
78.2Æ29.0
143.0Æ48.7
11.9Æ7.4
21.9Æ2.8
59.5Æ3.7
20.1Æ1.8
27.5Æ2.0
35.2Æ8.9
664Æ148
23.8Æ11.0
21.2Æ4.7
10.8Æ7.6
40.5Æ23.6
Compounds 6q and 6r were prepared in order to explore
the effect of a five-membered amine moiety versus the
corresponding six-membered ring. This structural
change had no effect on dopamine receptor affinity for
the benz-fused system (compare 6a and 6q), whereas a
dramatic reduction in D2 and D3 affinity, and an
increase in D4 affinity, was observed with the corre-
sponding 2-(3-pyridnyl)analogues (i.e., 6p vs 6r).
>1000
>1000
87Æ6
>1000
>1000
>1000
>1000
412Æ37
1d
1e
15.7Æ10.8
aMeanÆSEM, Ki values were determined by at least three experi-
bKi values for D2 receptors were measured on rat D2(long) expressed in
Sf9 cells using [125I]IABN as the radioligand.
cKi values for D3 receptors were measured on rat D3 expressed in Sf9
cells using [125I]IABN as the radioligand.
dKi values for s1 receptors were measured on guinea pig brain mem-
branes using [3H](+)-pentazocine as the radioligand.
eKi values for s2 receptors were measured on rat liver membranes
using [3H]-DTG as the radioligand in the presence of (+)-pentazocine.
ments.
Another interesting observation was the replacement of
the 5-bromo-2,3-dimethoxyphenyl group with the cor-
responding 4-bromo-1-methoxynaphthyl moiety. Our
previous studies have shown this substitution to result
in an increase in dopamine D3 receptor affinity and no
change in dopamine D2 receptor affinity for a series of
structurally-related benzamide derivatives.11 Surpris-
ingly, this structural change resulted in an unexpected
decrease in the affinity of the pyrrole analogues for both
dopamine D2 and D3 receptors (Table 1). Finally, the
affinity of compound 6a–r and 11a–d for sigma receptors
was also measured. With the exception of compound
11a, all compounds in this series displayed either a low
or negligible affinity for s1 and s2 receptors (Table 1).
contrast to methyl substitution in the 3-position of the
1,2,3,4-tetrahydroisoquinoline moiety (6d), which pos-
sessed an affinity for D2 and D3 receptors similar to 6b.
Surprisingly, addition of a phenyl group in the 1-posi-
tion of the 1,2,3,4-tetrahydroisoquinoline (6f) had a
lower effect on D2 and D3 receptor affinity than the
corresponding methyl substitution (i.e., compare 6b
versus 6f and 6b vs 6c).
Discussion
In an earlier study, we reported a series of benzamide
analogues possessing a high affinity for dopamine D2
and D3 receptors.16 Molecular modeling studies
revealed differences in the stereoelectronic properties of
the benzamide-binding region of the D2 and D3 recep-
tors. These subtle differences in the electrostatic prop-
erties of this class of compounds suggested that isoteric
replacement of the amide group with a heterocyclic ring
could produce in a shift in affinity of these compounds
for D2 and D2 receptors. These observations led to the
synthesis and evaluation of a series of imidazole analogues
as potential dopamine D3-selective ligands.12 The most
noteworthy compound to come from this follow-up
study was 1c (Fig. 1), which had a modest affinity for
dopamine D3 receptors and a D2/D3 selectivity ratio of
Compounds 6m, 6n, and 6o were prepared to explore
the effect of replacing the benzene ring of 6a with aro-
matic rings of increased steric demand. This substitution
generally led to a decreased in affinity for D3 receptors.
For example, the 4,6-benzo-1,2,3,4-tetrahydroisoquino-
line analogue (6m) had a significantly lower affinity for
D2 and D3 receptors relative to that of compound 6a. The
two 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]bindole analo-
gues, 6n and 6o, had a similar D2 affinity to 6a. Howev er,
both 6n and 6o had a lower affinity for D3 receptors
relative to 6a.
The most potent analogue in this series of compounds
was the diethylamino compound, 6g, which had a sub-

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R. H. Mach et al. / Bioorg. Med. Chem. 11 (2003) 225–233
Scheme 1. Reagents: (a) SOCl2/benzene; (b) Grignard reagent/CuBr/À70 ꢁC/THF, then aqueous acid; (c) 2 N HCl/methanol; (d) ammonium ace-
tate/ethanol; (e) formaldehyde/amine.
ꢀ7 (Table 1). While this research was being conducted, it
was reported that the isoteric substitution of a pyrrole ring
for the benzamide moiety of (S)-sultopride resulted in a
compound (i.e., DU 122290) with an improved D2/D3
selectivity ratio relative to the parent compound (Fig. 1).
This study led to the synthesis of a number of pyrrole-
based analogues displaying a high affinity and modest
selectivity for dopamine D3 versus D2 receptors.14,15

R. H. Mach et al. / Bioorg. Med. Chem. 11 (2003) 225–233
229
Scheme 2. Reagents (a) SOCl2/benzene; (b) Grignard reagent/CuBr/À70 ꢁC/THF, then aqueous acid; (c) ammonium acetate/ethanol; (d) formal-
dehyde/diethylamine.
The goal of the current study was to prepare a number
of pyrrole analogues of our imidazole-based com-
pounds. The results of the current study revealed that
the pyrrole analogues had a high affinity and greater
D2/D3 selectivity ratio than the corresponding imidazole
analogues. For example, a comparison of 5a versus 1a,
6a versus 1b, 6d versus 1c and 6j versus 1d reveals that
the corresponding pyrrole analogue has a higher affinity
for both D2 and D3 receptors and, with the exception of
1a and 5a, a higher D2/D3 selectivity ratio than the
corresponding imidazole analogue. Furthermore, the
imidazole analogue 1e was somewhat selective for D2
versus D3 receptors whereas the corresponding pyrrole,
6k, had a higher affinity for D3 receptors than D2
receptors. These data suggest that the pyrrole ring,
which is a p-excessive heteroaromatic ring, represents a
better isoteric substitution for the benzamide moiety
than an imidazole ring, which is a p-deficient hetero-
aromatic ring. Further studies are needed with other p-
deficient and p-excessive heteroaromatic ring systems to
test this hypothesis.
A second goal of this study was to determine the effect
of the location of the aromatic ring in the tertiary amine
moiety on D2-like dopamine receptor binding. Benz-
fused systems such as the 1,2,3,4-tertrahydroisoquino-
line analogues, 6a and 6b, displayed a high D3 affinity
and modest D2/D3 selectivity ratio. Increasing the
degree of steric bulk of the benz-fused system, such as in
the 4,5-benz-1,2,3,4-tetrahydroisoquinolone analogue,
6m, and the 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole
analogues, 6n and 6o, resulted in a reduction in affinity
for dopamine D2 and D3 receptors. Both the diethyl-
aminomethyl analogue, 6g, and the piperidinylmethyl
analogue, 6i, had a high D3 affinity and a 10-fold selec-
tivity for D3 versus D2 receptors. Substitution of the

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R. H. Mach et al. / Bioorg. Med. Chem. 11 (2003) 225–233
Table 2. In vitro binding data for dopamine D4 receptors
also had a relatively low affinity for D4 receptors when
compared to their affinity for dopamine D3 receptors.
With the exception of compound 11a, all compounds
had a low affinity for s1 and s2 receptors. The most
noteworthy compound identified in this study is 6p,
which has a high D3 affinity with excellent D2/D3 and
D4/D3 selectivity ratios. This compound is predicted to
be useful for studying the functional role of D3 receptors
in vivo.
Compd
Ki (nM)a
b
c
d
D2
D3
D4
D2/D3 ratioe D4/D3 ratiof
1
143Æ48.9 21.2Æ4.7 244Æ41
6.7
7.8
8.6
10.3
10
10.7
20.2
10.2
7.7
11.5
10.5
25.3
20
9.7
1182
296
28
22.4
6a
6b
6g
6i
29.5Æ1.5
33.4Æ6.0
3.8Æ1.2
40Æ20
3.9Æ0.5 98.5Æ51.7
6.6Æ0.6 0.64Æ0.2 12.9Æ4.5
19.1Æ2.6
1.9Æ0.6 18.4Æ4.1
6l
27.8Æ11.0 2.6Æ1.4 3.074Æ924
6p
6q
6r
86.8Æ7.3
17.4Æ1.2
4.3Æ2.5 1.272Æ598
1.7Æ0.6 47.9Æ19.0
1.69Æ15.1 21.9Æ2.8 491Æ65
Experimental
Chemistry
aMeanÆSEM, Ki values were determined by at least three experi-
ments.
bKi values for D2 receptors were measured on rat D2(long) expressed in
Sf9 cells using [125I]IABN as the radioligand.
cKi values for D3 receptors were measured on rat D3 expressed in Sf9
cells using [125I]IABN as the radioligand.
Melting points were measured on a Fisher–Johns melting
point apparatus and are uncorrected. Elemental analyses
were performed at Atlantic Microlab, Inc., Norcross, GA,
USA. Where molecular formulae were indicated, analyses
were found to be within 0.4% of the theoretical values,
dKi for inhibiting the binding of [125I]IABN to human D4,4 receptors.
eKi for D2/Ki for D3.
fKi for D4/Ki for D3.
1
unless otherwise noted. H NMR spectra were recorded
at 300 MHz on a Bruker ADVANCE300 spectrometer.
1
4-position of the piperidine ring with a phenyl group, 6j,
or a phenylmethyl group, 6k, resulted in a reduction in
D3 affinity relative to the unsubstituted compound, 6i.
However, substitution of the 4-position of 6i with a 4–2-
keto-1-benzimidazolinyl group, 6l, or the 2-position
with a 3-pyridyl group, 6p, resulted in compounds with
a high D3 affinity and moderate D2/D3 selectivity ratio
(Table 2). In addition, this substitution had a large
effect on the affinity of these compounds for dopamine
D4 receptors. That is, the affinity of 6i for D4 receptors
was 18.4 nM, whereas the affinity of 6l and 6p for the
dopamine D4 receptor was 3074 and 1272 nM, respec-
tively. The compound displaying the highest affinity and
selectivity for D3 versus D2 and D4 receptors is 6p,
which has a D2/D3 selectivity ratio of 20.2 and a D4/D3
selectivity ratio of 296.
All H NMR spectra were obtained in either CDCl3 or
DMSO-d6 and results are recorded as parts per million
(ppm) downfield to tetramethylsilane (TMS). The fol-
lowing abbreviations are used for multiplicity of NMR
signals: s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet, dd=double doublet, dt=double triplet,
dq=double quartet, br=broad. Mass spectrometry
studies (high resolution FAB) were conducted by the
Washington University Resource for Biomedical and
Bio-organic Mass Spectrometry, St. Louis, MO, USA.
All starting materials and solvents were purchased from
Aldrich, Fisher, or Lancaster and were used without
further purification.
Preparation of 2-(5-bromo-2,3-dimethoxyphenyl)-1H-
pyrrole (4b). A solution of 2-(2-bromoethyl)-1,3-dioxo-
lane (12.5 g, 69 mmol) in anhydrous tetrahydrofuran
(20 mL) was added to a stirred suspension of magne-
sium (3 g, 123 mmol) in anhydrous tetrahydrofuran (80
mL) and the reaction mixture was stirred at ambient
temperature for 30 min. The solution was transferred
under a nitrogen atmosphere to a three-necked round
bottom flask (500 mL) and cooled to 0 ꢁC. Powder
copper bromide (9.3 g, 65 mmol) was slowly added and
the reaction mixture was stirred at 5–15 ꢁC for 20 min.
The reaction mixture was cooled to À70 ꢁC (dry ice–
acetone) and a solution of 5-bromo-2,3-dimethylbenzoyl
chloride (15.37 g, 55 mmol) in anhydrous tetrahydro-
furan (100 mL) was added slowly over 15 min and the
reaction mixture was stirred at that temperature for an
additional 60 min. The dry ice–acetone bath was
removed and the mixture was stirred at ambient tem-
perature for 18 h. The mixture was poured into an ice
cold 2 N solution of aqueous HCl (200 mL) and the
mixture was extracted with ether (3Â100 mL). The
combined organic layers were dried (sodium sulfate)
and concentrated in vacuo to give an oil that was pur-
ified by silica gel column chromatography (hexane/ethyl
acetate, 8:2) to give 2b (10.89 g, 57%). This material was
dissolved in a 1:1 mixture of 2 N HCl in methanol and
the mixture was stirred at ambient temperature for 16 h.
The final goal of this structure–activity relationship
study was to replace the 5-bromo-2,3-dimethoxy phenyl
group with a 2-(4-bromo-1-methoxynaphthyl) group.
Our previous studies with structurally-related benza-
mide analogues indicated that this substitution resulted
in an improvement in the D3 affinity and D2/D3 selec-
tivity ratio of this class of compounds.11 An unexpected
result of this study was that the introduction of a 2-(5-
bromo-1-methoxy)naphthyl group into the pyrrole ser-
ies of compounds resulted in a dramatic reduction in
affinity for both D2 and D3 receptors. Molecular mod-
eling studies are currently being conducted to determine
the orientation of the aromatic rings within dopamine
D2 and D3 receptor binding sites.
In conclusion, a number of 2-(5-bromo-2,3-dimethoxy)-
1H-pyrrole analogues were prepared and their affinities
for dopamine D2, D3 and D4 receptors and sigma
receptors were measured using in vitro binding assays.
The pyrrole analogues had a higher affinity for D2 and
D3 receptors than the imidazole analogues reported in
an earlier study. Several of the pyrrole compounds had
a high affinity for dopamine D3 receptors and a D2/D3
selectivity ratio ranging from 10 to 20. These compounds

R. H. Mach et al. / Bioorg. Med. Chem. 11 (2003) 225–233
231
Volatile components were removed to give crude 3b as a
yellow oil. Ethanol (100 mL) and ammonium acetate
(19 g) were added and the reaction mixture was stirred
at reflux for 2 h. The mixture was poured into cold
water (250 mL) and washed with ethyl acetate (3Â100
mL). Volatile components were removed in vacuo and
the residue was purified by silica gel column chromato-
graphy (hexane/ethyl acetate, 9:10 to give 4b as a fluffy
white solid (8.95 g; 96%), mp 80–81 ꢁC. 1H NMR
(300 MHz, CDCl3) d 9.84 (s, 1H), 7.35 (d, 1H, J=2.4
Hz), 6.88–6.91 (m, 1H), 6.83 (d, 1H, J=1.9 Hz), 6.58–
6.60 (m, 1H), 6.25–6.30 9m, 1H), 3.88 s, 3H), 3.81 (s,
3H). Analysis (C12H12NO2Br) C, H, N.
in 98% yield, mp 84–86 ꢁC (free amine). 1H NMR
(300 MHz, CDCl3) d 9.91 (s, 1H), 7.31 (d, 1H, J=1.9
Hz), 6.81 (d, 1H, J=2.0 Hz), 6.60 (s, 1H), 6.51 (t, 1H,
J=2.9 Hz), 6.48 (s, 1H), 6.13 (t, 1H, J=2.9 Hz), 3.85 (s,
3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.73 (s, 2H), 3.72 (s, 3H),
3.57 (s, 2H), 2.82 (d, 2H, J=4.9 Hz), 2.77 (d, 2H, J=4.9
Hz). Analysis (C24H27N2O4Br) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(4,5-dimethoxy-2-
methyl-1,2,3,4-tetrahyroisoquinolino)methyl-1H-pyrrole (6c).
Compound 6c was obtained by the same method as
described for 5a in 49% yield, mp 164–166 ꢁC (oxalate
salt). 1H NMR (300 MHz, CDCl3) d 9.90 (s, 1H), 7.31–7.32
(m, 1H), 6.81–6.82 (m, 1H), 6.58 (s, 1H), 6.49–6.52 (m, 2H),
6.07–6.09 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H),
3.79 (s, 2H), 3.74 (s, 3H), 3.05–3.15 (m, 1H), 2.74–2.92 (m,
2-(2,3-Dimethoxyphenyl)-1H-pyrrole (4a). Compound
4a was obtained by the same method as described for 4b
in an overall yield of 17% from 2,3-dimethoxybenzoyl
.
4H), 1.40 (s, 3H). Analysis (C27H31N2O8 H2O) C, H, N.
chloride, mp 58–59 ꢁC. H NMR (300 MHz, CDCl3) d
1
7.22–7.26 (m, 1H), 7.02–7.08 (m, 1H), 6.88–6.90 (m,
1H), 6.73–6.77 (m, 1H), 6.59–6.62 (m, 1H), 6.59–6.62
(m, 1H), 6.27–6.30 (m, 1H), 3.90 (s, 3H), 3.84 (s, 3H).
Analysis (C12H13NO2) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(4,5-dimethoxy-8-
methyl-1,2,3,4-tetrahydroisoquinolino)methyl-1H-pyrrole
(6d). Compound 6d was obtained by the same method
as described for 5a in 67% yield, mp 164–166 ꢁC (oxa-
1
late salt). H NMR (300 MHz, CDCl3) d 11.11 (s, 1H),
2-(2-(4-Bromo-1-methoxynaphthyl)-1H-pyrrole
(11).
7.34 (s, 1H), 6.87 (s, 1H), 6.63–6.69 (m, 1H), 6.54–6.57
(m, 1H), 6.45 (s, 1H), 6.09–6.11 (m, 1H), 3.88 (s, 2H),
3.85 (s, 12H), 3.26 (s, 4H), 2.72–2.77 (m, 1H), 1.45 (s,
3H). Analysis (C27H31N2O8) C, H, N.
Compound 11 was obtained by the same method as
described for 4b in an overall yield of 28% from 8, mp
1
118–120 (dec.). H NMR (300 MHz, CDCl3) d 9.90 (s,
1H), 8.07–8.23 (m, 2H), 8.04 (s, 1H), 7.53–7.62 (m, 2H),
6.96–6.97 (m, 1H), 6.68–6.69 (m, 1H), 6.33–6.36 (m,
1H), 3.85 (s, 3H). Analysis (C15H12NOBr)C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(2-cyanomethyl-4,5-
dimethoxy - 1,2,3,4 - tetrahydroisoquinolino)methyl - 1H -
pyrrole (6e). Compound 6e was obtained by the same
method as described for 5a in 88% yield, mp 104–106 ꢁC
(free amine). 1H NMR (300 MHz, CDCl3) d 9.93 (s, 1H),
7.34 (d, 1H, J=2.3 Hz), 6.82 (d, 1H, J=2.3 Hz), 6.61 (s,
1H), 6.59 (s, 1H), 6.51 (t, 1H, J=3.0 Hz), 6.10 (t, 1H,
J=3.0 Hz), 3.87 (s, 6H), 3.85 (s, 5H), 3.82 (s, 3H), 3.08–
3.17 (m, 1H), 2.82–2.90 (m, 2H), 2.70–2.76 (m, 2H),
2.55–2.67 (m, 2H). Analysis (C26H28N3O4Br) C, H, N.
2-(2,3-Dimethoxyphenyl)-5-(1,2,3,4-tetrahydroisoquino-
lino)methyl-1H-pyrrole (5a). A solution of 1,2,3,4-tetra-
hydroisoquinoline (0.13 g, 1 mmol), 30% aqueous
formaldehyde (0.081 g) and acetic acid (0.08 g) in etha-
nol (25 mL) was stirred at ambient temperature for 30
min. At that time 2-(2,3-dimethoxyohenyl-1H-pyrrole
(0.2 g, 1.0 mmol) was added and reaction mixture was
stirred at ambient temperature for an additional 18 h.
The solvent was removed and the product was purified
by silica gel column chromatography (dichloromethane/
ethanol, 9.75:0.25) to give 5a as a white solid, which was
converted to the corresponding oxalate salt (0.33 g,
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(4,5-dimethoxy-2-
phenyl-1,2,3,4-tetrahydroisoquinolino)methyl-1H-pyrrole
(6f). Compound 6f was obtained by the same method
as described for 5a in 57% yield, mp 121–123 ꢁC (free
amine). 1H NMR (300 MHz, CDCl3) d 9.83 (s, 1H),
7.22–7.38 (m, 6H), 6.80 (d, 1H, J=2.2 Hz), 6.59 (s, 1H),
6.46 (t, 1H, J=2.9 Hz), 6.16 (s, 1H), 6.03 (t, 1H, J=2.9
Hz), 3.88 (s, 3H), 3.85 (s, 3H), 3.77 (s, 5H), 3.59 (s, 3H),
3.40 (s, 1H), 2.96–3.16 (m, 2H), 2.53–2.73 (m, 2H).
Analysis (C30H31N2O4Br) C, H, N.
75%), mp 172–174 ꢁC. H NMR (300 MHz, CDCl3) d
1
6.88–7.21 (m, 7H), 6.70–6.73 (m, 1H), 6.52–6.54 (m,
1H), 6.12–6.14 (m, 1H), 3.86 (s, 3H), 3.74 (s, 2H), 3.73
(s, 3H), 3.67 (s, 2H), 2.89–2.93 (m, 2H), 2.77–2.81 (m,
2H). Analysis (C24H26N2O6) 1=2 H2O) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(1,2,3,4-tetrahydro-
isoquinolino)methyl-1H-pyrrole (6a). Compound 6a was
obtained by the same method as described for 5a in
69% yield, mp 128–130 ꢁC (HCl salt). 1H NMR
(CDCl3) d (300 MHz, CDCl3) d 7.32 (d, 1H, J=2.3 Hz),
7.10–7.15 (m, 4H), 6.99–7.01 (m, 1H), 6.81 (d, 1H,
J=2.3 Hz), 6.51–6.53 (m, 1H), 6.13–6.16 (m, 1H), 3.85
(s, 6H), 3.73 (s, 2H), 3.64 (s, 2H), 2.93–2.95 (m, 2H),
2.83–2.85 (m, 2H); ms (C22H23N2O2Br, Mr=426.0943)
427.0996 (M+1).
Preparation of 2-(5-bromo-2,3-dimethoxyphenyl)-5-di-
ethylaminomethyl-1H-pyrrole (6g). Compound 6g was
obtained by the same method as described for 5a in
70% yield, mp 140–141 ꢁC (oxalate salt). 1H NMR
(300 MHz, CDCl3) d 9.95 (s, 1H), 7.31–7.32 (m, 1H),
6.80–6.81 (m, 1H), 6.48–6.50 (m, 1H), 6.04–6.05 (m,
1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.64 (s, 2H), 2.55 (q, 4H,
J=7.2 Hz), 1.06 (t, 6H, J=7.1 Hz). Analysis
(C19H25N2O6Br) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(4,5-dimethoxy-1,2,3,4-
tetrahydroisoquinolino)methyl-1H-pyrrole (6b). Compound
6b was obtained by the same method as described for 5a
2-(5-Bromo-2,3-dimethoxyphenyl)-5-diphenylmethylamino-
methyl-1H-pyrrole (6h). Compound 6h was obtained by
the same method as described for 5a in 50% yield, mp

232
R. H. Mach et al. / Bioorg. Med. Chem. 11 (2003) 225–233
247 ꢁC (dec., oxalate salt). H NMR (300 MHz, CDCl3)
d 7.39–7.42 (m, 5H), 7.30–7.35 (m, 5H), 7.20–7.25 (m,
2H), 6.81 (d, 1H, J=6.0 Hz), 6.46 (t, 1H, J=5.1 Hz),
6.09 (t, 1H, J=5.1 Hz), 3.91 (s, 3H, 3.77 (s, 3H), 3.60 (s,
4H), 3.57 (s, 2H).
7.47 (d, 1H, J=7.1 Hz), 7.32 (d, 1H, J=2.2 Hz), 7.26–
7.30 (m, 1H), 7.08–7.15 (m, 2H), 6.81 (d, 1H, J=2.2
Hz), 6.52 (t, 1H, J=3.0 Hz), 6.13 (t, 1H, J=3.0 Hz),
3.85 (s, 3H), 3.81 (s, 2H), 3.74 (s, 3H), 3.68 (s, 2H),
2.81–2.95 (m, 4H). Analysis (C24H24N3O2Br) C, H, N.
1
2-(5-Bromo-2,3-dimethoxyphenyl)-5-piperinylmethyl-1H-
pyrrole (6i). Compound 6i was obtained by the same
method as described for 5a in 87% yield, mp 182–184 ꢁC
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(1-(1,2,3,4-tetrahydro-
9H-pyrido[3,4-b]indole)methyl)-1H-pyrrole (6o). Com-
pound 6o was obtained by the ꢁsame method as described
for 5a in 89% yield, mp 82–83 C (free amine). 1H NMR
(300 MHz, CDCl3) d 9.93 (s, 1H), 7.54 (s, 1H), 7.32 (d,
2H, J=2.3 Hz), 7.18 (d, 1H, J=8.6 Hz), 6.93 (d, 1H,
J=2.3 Hz), 6.77–6.82 (m, 2H), 6.52 (t, 1H, J=3.0 Hz),
6.13 (t, 1H, J=3.0 Hz), 3.86 (s, 6H), 3.81 (s, 2H), 3.74
(s, 3H), 3.68 (s, 2H), 2.93 (t, 2H, J=5.6 Hz), 2.80 (t, 2H,
J=5.6 Hz). Analysis (C25H26N3O3Br) C, H, N.
1
(oxalate salt). H NMR (300 MHz, CDCl3) d 9.91 (m,
1H), 7.30–7.31 (m, 1H), 6.80–6.82 (m, 1H), 6.46–6.48
(m, 1H), 6.03–6.05 (m, 1H), 3.88 (s, 3H), 3.79 (s, 3H),
3.51 (s, 2H), 2.40 (s, 4H), 1.51–1.61 (m, 4H), 1.43 (s,
2H). Analysis (C20H25N2O6Br) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(4-phenylpiperidinyl)-
methyl-1H-pyrrole (6j). Compound 6j was obtained by
the same method as described for 5a in 71% yield, mp
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(2-(3-pyridyl)-piper-
idinyl)methyl-1H-pyrrole (6p). Compound 6p was
obtained by the same method as described for 5a in
73% yield, mp 139–140 ꢁC (free amine). 1H NMR
(300 MHz, CDCl3) d 9.84 (s, 1H), 8.62 (s, 1H), 8.48–8.50
(m, 1H), 7.77–7.80 (m, 1H), 7.24–7.31 (m, 2H), 6.82 (d, 1H,
J=2.2 Hz), 6.43 (t, 1H, J=3.0 Hz), 5.94 (t, 1H, J=3.0
Hz), 3.91 (s, 3H), 3.84 (s, 3H), 3.61 (d, 2H, J=14.2 Hz),
316–3.21 (m, 2H), 3.02–3.10 (m, 3H), 2.03–2.11 (m, 2H),
1.76–1.84 (m, 2H). Analysis (C23H26N3O2Br) C, H, N.
ꢁ
1
158–160 C (oxalate salt). H NMR (300 MHz, CDCl3)
d 9.91 (s, 1H), 7.17–7.33 (m, 6H), 6.81–6.82 (m, 1H),
6.48–6.50 (m, 1H) 6.06–6.08 (m, 1H), 3.88 (s, 3H), 3.80
(s, 3H), 3.59 (s, 2H), 3.00–3.05 (m, 2H), 2.47–2.55 (m,
1H), 2.08–2.16 (m, 2H), 1.75–1.82 (m, 4H). Analysis
(C26H29N2O6Br) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(4-phenylmethylpiper-
idinyl)methyl-1H-pyrrole (6k). Compound 6k was
obtained by the same method as described for 5a in
55% yield, mp 137–139 ꢁC (oxalate salt). 1H NMR
(300 MHz, CDCl3 d 9.89 (s, 1H), 7.11–7.31 (m, 6H),
6.81–6.82 (m, 1H), 6.46–6.48 (m, 1H), 6.01–6.03 (m,
1H), 3.88 (s, 3H), 3.78 (s, 3H), 3.52 (s, 2H), 2.86–2.89
(m, 2H), 2.52–2.54 (m, 2H), 1.91–1.98 (m, 2H), 1.53–
1.61 (m, 3H), 1.22–1.34 (m, 2H). Analysis
(C27H31N2O6Br) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(3,4-benzopyrrolidi-
nyl)methyl-1H-pyrrole (6q). Compound 6q was
obtained by the same method as described for 5a in
37% yield, mp 185–187 ꢁC (free amine). 1H NMR
(300 MHz, CDCl3) d 9.89 (s, 1H), 7.32 (d, 1H, J=2.3
Hz), 7.19 (s, 4H), 6.81 (d, 1H, J=2.3 Hz), 6.52 (t, 1H,
J=3.1 Hz), 6.13 (t, 1H, J=3.1 Hz), 3.97 (s, 4H), 3.93 (s,
2H), 3.86 (s, 3H), 3.77 (s, 3H). Analysis
(C23H23N2O6Br) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(4-(2-keto-1-benz-
imidazolinyl)piperidinyl)methyl-1H-pyrrole (6l). Compound
6l was obtained by the same method as described for 5a
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(2-(3-pyridyl)pyrro-
lidinyl)methyl-1H-pyrrole (6r). Compound 6r was
obtained by the same method as described for 5a in
73% yield, mp 71–74 ꢁC (dioxalate salt). 1H NMR
(300 MHz, CDCl3) d 8.61 (s, 1H), 8.48–8.50 (m, 1H),
7.76–7.83 (m, 1H), 7.29–7.38 (m, 3H), 6.82 (d, 1H,
J=2.2 Hz), 6.44 (t, 1H, J=3.1 Hz), 6.00 (s, 1H), 3.91 (s,
3H), 3.87 (s, 3H), 3.20–3.50 (m, 5H), 2.25–2.45 (m, 4H).
in 46% yield, mp 189–191 ꢁC (free amine). H NMR
1
(300 MHz, CDCl3) d 9.90 (s, 1H), 8.80 (s, 1H), 7.33 (d,
1H, J=2.3 Hz), 7.07–7.09 (m, 3H), 6.83 (d, 1H, J=2.3
Hz), 6.49 (t, 1H, J=3.1 Hz), 6.10 (t, 1H, J=3.1 Hz),
3.90 (s, 3H), 3.84 (s, 3H), 3.61 (s, 2H), 3.05–3.10 (m,
2H), 2.42–2.52 (m, 2H), 2.15–2.25 (m, 2H), 1.80–1.87
(m, 2H). Analysis (C25H27N4O3Br) C, H, N.
.
Analysis (C26H28N3O10Br 2H2O) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(4,5-benzo-1,2,3,4-
tetrahydroisoquinolino)methyl-1H-pyrrole (6m). Com-
pound 6m was obtained by the same method as descri-
2-(2-(4-Bromo-1-methoxynapthyl)-5-(4,5-dimethoxy-1,2,3,4-
tetrahydroisoquinolino)methyl-1H-pyrrole (11a). Com-
pound 11a was obtained by the same method as described
for 5a in 78% yield from 10, mp 196–198 ꢁC (oxalate
salt). 1H NMR (300 MHz, CDCl3) d 10.05 (s, 1H), 8.05–
8.18 (m, 2H), 8.04 (s, 1H), 7.50–7.60 (m, 2H), 6.62 (s,
2H), 6.50 (s, 1H), 6.19–6.23 (m, 1H), 3.85 (s, 3H), 3.80
(s, 3H), 3.78 (s, 3H), 3.62 (s, 2H), 2.80–2.90 (m, 6H).
Analysis (C29H29N2O7Br) C, H, N.
bed for 5a in 50% yield, mp 88–89 ꢁC (free amine). H
1
NMR (300 MHz, CDCl3) d 9.88 (s, 1H), 7.70 (d, 2H,
J=8.2 Hz), 7.39 (t, 2H, J=7.6 Hz), 7.31 (d, 1H, J=2.3
Hz), 7.16 (d, 2H, J=7.1 Hz), 6.79 (d, 1H, J=2.3 Hz),
6.53 (t, 1H, J=3.1 Hz), 6.15 (t, 1H, J=3.1 Hz), 4.01 (s,
4H), 3.85 (s, 2H), 3.82 (s, 3H), 3.60 (s, 3H). Analysis
(C27H25N2O6Br) C, H, N.
2-(5-Bromo-2,3-dimethoxyphenyl)-5-(1,2,3,4-tetrahydro-
9H-pyrido[3,4-b]indole)methyl)-1H-pyrrole (6n). Com-
pound 6n was obtained by the sameꢁmethod as described
2-(2-(4-Bromo-1-methoxynaphthyl)-5-(4-(2-keto-1-benz-
imidazolin-yl)piperidinyl)methyl-1H-pyrrole (11b). Com-
pound 11b was obtained by the same method as
described for 5a in 75% yield from 10, mp 202 ꢁC (dec.,
1
for 5a in 95% yield, mp 100–101 C (free amine). H
1
NMR (300 MHz, CDCl3) d 9.92 (s, 1H), 7.65 (s, 1H),
free amine). H NMR (300 MHz. CDCl3) d 8.12–8.18

R. H. Mach et al. / Bioorg. Med. Chem. 11 (2003) 225–233
233
(m, 2H), 8.03 (s, 1H), 7.52–7.61 (m, 2H), 7.30–7.32 (m,
Acknowledgements
1H), 7.07 (s, 4H), 6.58–6.60 (m, 1H), 6.17–6.20 (m, 1H),
4.36–4.40 (m, 1H) 3.90 (s, 3H), 3.74 (s, 2H), 3.11–3.22
(m, 2H), 2.48–2.55 (m, 2H), 2.20–2.28 (m, 2H), 1.83–
1.87 (m, 2H). Analysis (C28H27N4O2Br) C, H, N.
This research was supported by PHS grants DA 09142,
DA 09147 and DA 12647 from the National Institute on
Drug Abuse.
2-(2-(4-Bromo-1-methoxynaphthyl)-5-(2-(3-pyridyl)-piper-
idinyl)methyl-1H-pyrrole (11c). Compound 11c was
obtained by the same method as described for 5a in
91% yield from 10, mp 85–87 ꢁC (oxalate salt). 1H
NMR (300 MHz, CDCl3) d 9.90 (s, 1H), 8.70 (s, 1H),
8.50–8.53 (m, 1H), 8.10–8.16 (m, 2H), 8.00 (s, 1H),
7.80–7.83 (m, 1H), 7.50–7.60 (m, 2H), 7.27–7.33 (m, 1H)
6.53–6.57 (m, 1H), 5.98–6.02 (m, 1H), 3.88 (s, 3H),
3.65–3.70 (m, 2H), 3.08–3.25 (m, 4H), 2.05–2.15 (m,
1H), 1.58–1.85 (m, 4H). Analysis (C30H30N3O9Br) C, H,
N.
References and Notes
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2-(5-Bromo-2,3-dimethoxyphenyl)-5-(3,4-benzopyrrolidi-
nyl)methyl-1H-pyrrole (11d). Compound 11d was
obtained by the same method as described for 5a in
42% yield from 10, mp 193–194 ꢁC (free amine). 1H
NMR (300 MHz, CDCl3) d 10.05 (s, 1H), 8.05–8.15 (m,
2H), 8.03 (s, 1H), 7.50–7.55 (m, 2H), 7.20 (s, 4H), 6.60–
6.65 (m, 1H), 6.19–6.22 (m, 1H), 4.01 (s, 4H), 3.99 (s,
2H), 3.83 (s, 3H). Analysis (C26H23N2O5Br) C, H, N.
11. Huang, Y.; Luedtke, R. R.; Freeman, R. A.; Wu, L.;
Mach, R. H. J. Med. Chem. 2001, 44, 1815.
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Healy, M. A. M.; Johnson, C. N.; Markwell, R. E.; Nash,
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In vitro binding assays
In vitro dopamine receptor binding studies were con-
ducted using membranes prepared from (a) Spodoptera
frugiperda (Sf9) cells that express a high density of either
rat D2(long) or rat D3 or (b) HEK 293 cells expressing
human D4.4 receptors. The radioligand used was
[
125I]IABN and the assay conditions have been pre-
viously described.17 The Ki values were calculated from
the corresponding IC50 values using the method of
Cheng and Prusoff.18
In vitro s1 receptor binding affinity was measured in guinea
pig brain membranes (Rockland Biological, Gilbertsville,
PA, USA) using the s1-selective radioligand, [3H](+)-
pentazocine (DuPont-NEN, Bilerica, MA, USA)
according to the methods as described previously.19 In
vitro s2 receptor binding affinity was measured in rat
liver membranes using [3H]DTG (DuPont-NEN, Bilerica,
MA, USA) as the radioligand in the presence of (+)-
pentazocine (100 nM) as previously described.19