Synthesis and structure-activity relationships of naphthamides as dopamine D3 receptor ligands

Article abstract of DOI:10.1021/jm0100077

A series of naphthamides were synthesized, and the affinities of these compounds were determined for dopamine D₂ and D₃ receptors using radioligand binding techniques. The naphthamide compounds that were prepared include N-(1- alkylp

Full text of DOI:10.1021/jm0100077

J . Med. Chem. 2001, 44, 1815-1826
1815
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of Na p h th a m id es a s Dop a m in e
D3 Recep tor Liga n d s
Yunsheng Huang,† Robert R. Luedtke,‡ Rebekah A. Freeman,‡ Li Wu,† and Robert H. Mach*,†,§
Department of Radiology-PET Center and Department of Physiology & Pharmacology, Wake Forest University School of
Medicine, Winston-Salem, North Carolina 27157, and Department of Pharmacology and Neuroscience, University of North
Texas Health Science Center, Fort Worth, Texas 76107
Received J anuary 5, 2001
A series of naphthamides were synthesized, and the affinities of these compounds were
determined for dopamine D2 and D3 receptors using radioligand binding techniques. The
naphthamide compounds that were prepared include N-(1-alkylpiperidin-4-yl)-4-bromo-1-
methoxy-2-naphthamides (1-6), (S)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphth-
amides (7-12), (R)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (13-18), (S)-
N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (19-25), (R)-N-(1-alkyl-
2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (26-31), and N-(9-alkyl-9-azabicyclo-
[3.3.1]nonan-3â-yl)-4-bromo-1-methoxy-2-naphthamides (32, 33). The results of in vitro radio-
ligand binding studies indicated that the majority of the naphthamide analogues bound with
high affinity at both the D2 and D3 dopamine receptor subtypes and most of the compounds
demonstrated some selectivity for the dopamine D3 dopamine receptor subtype. These results
demonstrated that both the structure of the central amine moiety (piperidine, pyrrolidine, and
9-azabicyclo[3.3.1]nonane) ring and the N-(alkyl) substitution on the amine significantly effects
the binding affinity at D2 and D3 dopamine receptors. The bulkiness of the N-(1-alkyl)
substituent was found to (a) have no effect on pharmacologic selectivity, (b) increase the affinity
at D3 receptors, or (c) decrease the affinity at D2 receptors. The most potent analogue in this
series was (S)-N-(1-cycloheptylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamide (10), which
had equilibrium dissociation (Ki) values of 1.8 and 0.2 nM for D2 and D3 receptors, respectively.
The most selective analogue was (R)-N-(1-cycloheptyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-
2-naphthamide (30), which had Ki values of 62.8 and 2.4 nM for D2 and D3 receptors,
respectively. Radioligand binding results for σ receptors indicated that the structure of the
amine moiety and the N-(1-alkyl) substitutions also significantly influence the affinity and
selectivity of these compounds at the σ1 and σ2 sigma receptor subtypes. The two naphthamides
containing a 9-azabicyclo[3.3.1]nonan-3â-yl central ring were found to be selective for σ2
receptors.
In tr od u ction
Recent studies have indicated that the dopamine D3
receptor subtype may be an important biological target
for pharmacotherapeutic agents used in the treatment
of schizophrenia2,8 and/or substance abuse.3,9 Essentially
all clinically effective neuroleptics are antagonists at
dopamine D2 and D3 receptors.10 Therefore, it has been
hypothesized that the blockade of dopamine D2 receptors
in the caudate putamen region of the brain may be
responsible for extrapyramidal side effects,11 while the
blockade of dopamine D2/D3 receptors in the limbic
regions of the brain may be associated with anti-
psychotic effects.10,12 The localization of the D3 receptors
in the limbic regions of the brain suggests that this
receptor subtype may be an appropriate pharmacologic
target for the development of antipsychotic agents with
lower risk of extrapyramidal side effects.8,13
Multiple neurological and neuropsychiatric disorders,
including Parkinson’s disease, Tourette’s syndrome,
tardive dyskinesia, schizophrenia, schizoaffective dis-
orders, and addiction to psychostimulants, appear to
reflect disturbances of the dopaminergic system.1-3
Molecular genetic studies have identified five subtypes
of dopamine receptors: D1, D2, D3, D4, and D5.4,5 The
dopamine receptor subtypes are generally grouped into
two families of dopamine receptors, D1-like (D1 and D5)
and D2-like (D2, D3, and D4) receptors based on similar
pharmacologic properties and primary structure
homology.4-7 However, a complete understanding of the
pharmacological and physiological roles of the dopamine
receptor subtypes has been hindered by a lack of
compounds with selectivity for each individual dopam-
ine receptor subtype.
Recent studies have also suggested that dopamine D3
receptors play an important role in mediating the
reinforcing effects of the psychostimulant cocaine.14,15
Selective dopamine D3 receptor antagonists have been
found to block the reinforcing effects of cocaine in animal
studies. Therefore, D3 receptor selective compounds may
prove to be useful for the treatment of individuals who
abuse cocaine.15,16
* To whom correspondence should be addressed. E-mail: rmach@
wfubmc.edu. Phone: 336-716-7462. Fax: 336-716-5639.
† Department of Radiology-PET Center, Wake Forest University
School of Medicine.
‡ University of North Texas Health Science Center.
§ Department of Physiology & Pharmacology, Wake Forest Univer-
sity School of Medicine.
10.1021/jm0100077 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/31/2001

1816 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Huang et al.
Ch a r t 1
Sch em e 1a
a
Reagents: (a) (CF3CO)2O/CH2Cl2, room temperature; (b)
ketone/H2/PdOH/C, Pd/C; (c) NH4OH/CH3OH; (d) 4-bromo-1-
methoxy-2-napthoyl chloride/CH2Cl2/Et3N.
N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphth-
amides, and related analogues, for dopamine D2 and D3
receptors. The affinity of the new naphthamide ana-
logues was also determined for σ1 and σ2 receptors
because previous studies indicated that benzamide
analogues may bind with high affinity at σ recep-
tors.24,43,44 In addition, binding at σ receptor subtypes,
particularly the σ1 receptor, may be a component of
clinical efficacy of a number of antipsychotics.29,30 The
results of this study led to the identification of a number
of compounds having a high affinity for dopamine D2
versus D3 receptors and varying affinity for σ1 and σ2
receptors.
Ch em istr y
The synthesis of N-(1-alkylpiperidin-4-yl)-4-bromo-1-
methoxy-2-naphthamide is outlined in Scheme 1.
4-Amino-1-benzylpiperidine was treated with trifluoro-
acetic anhydride, followed by debenzylation and reduc-
tive alkylation using a combination of Pd hydroxide/C
and Pd/C as the cocatalyst. After removal of the
trifluoroacetyl group, the 4-amino-1-alkylpiperidine
was condensed with 4-bromo-1-methoxy-2-naphthoyl
chloride to afford compounds 1-6.
The synthetic strategy for the preparation of (S)-1-
benzyl-3-(tert-butoxycarbonylamino)pyrrolidine (IIa), (R)-
1-benzyl-3-(tert-butoxycarbonylamino)pyrrolidine (IIb),
(S)-N-(1-benzyl-2-pyrrolidinylmethyl)-tert-butoxycarb-
amide (IIc), and (R)-N-(1-benzyl-2-pyrrolidinylmethyl)-
tert-butoxycarbamide (IId ) is shown in Scheme 2. The
hydroxyl group was mesylated with mesyl chloride,
followed by reaction with sodium azide, reduction with
lithium aluminum hydride, and condensation with di-
tert-butyl dicarbonate to give the corresponding inter-
mediate (IIa -IId ). The intermediates (IIa -IId ) then
underwent the same procedures shown for Ia of Scheme
1 to afford compounds 7-12, 13-18, 19-25, and 26-
31.
The benzamides are a class of drugs that have
nanomolar to subnanomolar affinity for D2-like dopa-
mine receptors. Representative compounds include
sulpiride,17 clebopride,18 GR103691,19 and NGB2094
(Chart 1).20 We previously reported a panel of benz-
amide analogues that bound with high affinity at
dopamine D2 and D3 receptors.21-23 In those studies our
research efforts focused on the replacement of the
substituents on the benzamide aromatic ring and on the
modifications of the N-phenylalkyl group on the basic
nitrogen. The results of those studies led to analogues
that were more selective for dopamine D2 receptors than
for D3 receptors.
The goal of the current study was to explore the
structure-activity relationships of the N substituent of
a series of naphthamides as candidate D3 receptor
selective ligands. Naphthamides have been identified
as potent dopamine D2 and D3 receptor ligands.23,24 We
previously reported that replacement of the phenyl ring
of the benzamide D2/D3 receptor ligands with a naphthyl
ring to form naphthamides resulted in an increased
affinity for D3 receptors.23 In addition, a series of (S)-
N-(1-alkyl-3-pyrrolidinyl)-5-chloro-4-[(cyclopropylcarbo-
nyl)amino]-2-methoxybenzamide analogues were re-
ported to have high affinity and selectivity for D3
receptors.25 In vitro binding studies with those com-
pounds indicated that an increase in the bulkiness and
the lipophilicity of the N-alkyl group on the basic
nitrogen consistently enhanced the selectivity of the
compounds at D3 receptors. In this report we describe
the synthesis and binding properties of a new series of
Compounds 32 and 33 were prepared from the cor-
responding 3â-amino-9-cyclohexyl-9-azabicyclo[3.3.1]-
nonane and 3â-amino-9-cycloheptyl-9-azabicyclo[3.3.1]-
nonane, respectively, by condensing with 4-bromo-1-
methoxy-2-naphthoyl chloride. 3â-Amino-9-cyclohexyl-
9-azabicyclo[3.3.1]nonane and 3â-amino-9-cycloheptyl-
9-azabicyclo[3.3.1]nonane were obtained by a Mannich
reaction to form the corresponding 9-cycloalkyl-9-
azabicyclo[3.3.1]non-3-one, 34.18 This process was fol-
lowed by conversion into the corresponding oxime, 35.
Reduction with sodium in amyl alcohol gave the desired
exo amine, 36, in quantitative yield (Scheme 3).

Naphthamides as Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1817
Sch em e 2a
a
Reagents: (a) methanesulfonyl chloride/Et3N/THF, 0°C; (b) NaN3/DMF, reflux; (c) LiAlH4/THF, reflux; (d) (BOC)2O/CH2Cl2.
Sch em e 3a
tions were analogous to those previously described.21
In vitro σ1 receptor binding affinity was measured using
guinea pig brain membranes (Rockland Biological,
Gilbertsville, PA) and the σ1-selective radioligand [3H]-
(+)-pentazocine (DuPont-NEN, Bilerica, MA) according
to the methods previously described.27 In vitro σ2
receptor affinity was determined using rat liver mem-
branes with [3H]DTG (DuPont-NEN, Bilerica, MA) as
the radioligand. The equilibrium dissociate constants,
Ki values, were calculated from the corresponding IC50
values using the method of Cheng and Prusoff.26
Resu lts a n d Discu ssion
A common feature of drugs used clinically as anti-
psychotics is that they are antagonists at both the D2
and D3 dopamine receptor subtypes. The goal of the
studies presented in this communication was to explore
variations in the structure of naphthamides in an effort
to identify novel compounds that bind with selectivity
at the D3 receptor compared to the D2 dopamine receptor
subtype. It has been hypothesized that the antipsychotic
effects of the neuroleptics may be due to the antagonism
of both dopamine D2 and D3 receptors in the limbic
a
Reagents: (a) as in ref 18; (b) NH2OH‚HCl/EtOH, reflux; (c)
Na/amyl alcohol, reflux; (d) 4-bromo-1-methoxy-napthyl chloride.
P h a r m a cologica l Assa ys
In vitro dopamine receptor radioligand binding stud-
ies were performed using membranes prepared from
Spodoptera frugiperda (Sf9) cells that express high
levels of either D2 (long) or D3 dopamine receptors. The
radioligand used was [125I]IABN, and the assay condi-

1818 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Huang et al.
Ta ble 1. Dopamine D2 and D3 Receptor Binding Profiles of N-(1-Alkylpiperidin-4-yl)-4-bromo-1-methoxy-2-naphthamides
a
a
Ki (nM)
Ki (nM)
b
c
d
e
f
R
D2
D3
D2/D3
σ1
σ2
1
2
3
4
5
6
benzyl
5.5 ( 2.8
210 ( 37.1
94 ( 22
1.1 ( 0.4
899 ( 22
430 ( 54
58 ( 17
1431 ( 350
92 ( 31
5
5.6 ( 0.5
1.2 ( 0.2
1.1 ( 0.1
1.1 ( 0.2
1.9 ( 0.1
121 ( 13
35 ( 3
cyclopentyl
cyclohexyl
cycloheptyl
bicyclo[3.3.1]nonan-9-yl
2-adamantyl
0.2
0.2
0.4
0.5
1.0
6.8 ( 0.6
2.1 ( 0.3
2.6 ( 0.3
2.4 ( 0.7
55 ( 7
23 ( 6
771 ( 175
96 ( 46
a
b
Mean ( SEM, Ki values were determined from at least three experiments. Ki values for D2 receptors were measured on rat D2(long)
expressed in Sf9 cells using [125I]IABN as the radioligand. c Ki values for D3 receptors were measured on rat D3 expressed in Sf9 cells
using [125I]IABN as the radioligand. Ki for D2 receptor/Ki for D3 receptor. e Ki values for σ1 receptors were measured on guinea pig brain
d
membranes using [3H](+)-pentazocine as the radioligand. f Ki values for σ2 receptors were measured on rat liver membranes using [3H]-
DTG as the radioligand in the presence of (+)-pentazocine.
region of the brain, while the extrapyramidal side effects
result after chronic blockade of the D2 receptors in the
nigrostriatal region. The long-term goal would be to
develop a new generation of antipsychotic drugs that
retain clinical efficacy without extrapyramidal side
effects. However, it has been difficult to develop com-
pounds that bind with substantially higher affinity at
D3 receptors than at the D2 dopamine receptor subtype
because the amino acid sequences of the transmembrane
spanning regions that construct the neurotransmitter
binding sites of these two G protein associated receptor
subtypes are 75-80% homologous.
Recent studies have suggested that the σ1 receptors
may also play a role in the regulation of psychosis
because a number of antipsychotic drugs bind with
affinity at σ1 receptors rather than at dopamine recep-
tors.29 This observation has led to the hypothesis that
the pharmacologic blockade of σ1 receptors may be
important for antipsychotic activity, without contribut-
ing to the extrapyramidal side effects of antipsychotic
drugs.30 In addition, antagonism of σ1 receptors may
correlate with the ability to block the development of
sensitization to cocaine and other psychostimulants.31,32
Recent clinical studies using the σ receptor selective
ligand panamesine in patients with schizophrenia re-
ported an improvement in psychometric variables with
no observed extrapyramidal side effects.33 Therefore, σ1
receptor antagonists may play a role in preventing
schizophrenics from deteriorating or relapsing.32 Since
the blockade of D2 receptors, D3 receptors, and σ1
receptors has been indicated to be associated with the
antipsychotic effects of many neuroleptics, a compound
that possesses (a) high affinity for D3 dopamine recep-
tors and σ1 receptors with (b) moderate to low affinity
for D2 dopamine receptors and σ2 receptors may poten-
tially be useful for the treatment of schizophrenia. The
results of radioligand binding studies designed to de-
termine the affinity of naphthamides at D2 and D3
dopamine receptors and σ1 and σ2 receptors are shown
in Tables 1-6.
than the cycloalkyl groups of the other compounds in
this series (Table 1), has high affinity (Ki ) 1-5 nM)
for both D2 and D3 dopamine receptors with a 5-fold
selectivity for D3 receptors. This result is in agreement
with our previously published results of the N-(9-benzyl-
9-azabicyclo[3.3.1]nonan-3â-yl) benzamide analogues.23
The affinity for D2 and D3 receptors (compounds 2-6)
decreased when the benzyl group of compound 1 was
replaced by cycloalkyl groups. This result is consistent
with the D2-like dopamine receptor binding site model
proposed by Rognan and co-workers.28 In the Rognan
model the D2 receptor has three aromatic binding
regions within the neurotransmitter binding site, termed
AR1, AR2, and AR3, and a subsite that is complemen-
tary to a basic nitrogen atom of the central ring. The
naphthamide aromatic moiety of compounds 1-6 is
hypothesized to interact with the AR1 region, while the
benzyl group of compound 1 would likely bind to either
the AR2 or AR3 region. On the basis of this model, the
cycloalkyl moieties of compounds 2-6 would not be
accommodated well within either the AR2 or AR3
region.
The results of σ receptor binding studies indicated
that compounds 2-5 had higher affinity (Ki ranged from
1 to 7 nM) for both σ1 and σ2 receptors than for D2 or
D3 receptors. Compounds 1 and 6 had moderate to low
affinity (Ki values of 6-120 nM) for σ receptors. There-
fore, in this series of compounds the benzyl group played
a crucial role in D2-like dopamine receptor binding
affinity and selectivity with respect to σ receptors. Of
this series of six compounds, compound 1 had the most
pharmacologically desirable properties because (a) it
bound D3 receptors with nanomolar affinity, (b) it was
5-fold-selective for the D3 receptor compared to the
selectivity for D2 and σ1 receptors, and (c) it was 32-
fold-selective for D3 dopamine compared to the selectiv-
ity for the σ2 receptor.
Ohmori and co-workers reported a series of (S)-N-(1-
benzylpyrrolidin-3-yl)-5-chloro-4-[(cyclopropylcarbonyl)-
amino]-2-methoxybenzamide compounds that bound
with high affinity and selectivity at D3 dopamine
receptors.25 Therefore, either a (S)- or a (R)-1-alkyl-
pyrrolidin-3-yl moiety was incorporated into our naphth-
amide analogues to determine the effect of these groups
on the affinity and selectivity of the naphthamide
Except for compound 1, the piperidine series of
naphthamides exhibited relatively low affinity (Ki values
greater than 20 nM) for both D2 and D3 receptors.
Compound 1, which has a benzyl group substitution on
the basic nitrogen of the central piperidine ring rather

Naphthamides as Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1819
Ta ble 2. Dopamine D2 and D3 Receptor Binding Profiles of (S)-N-(1-Alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides
a
a
Ki (nM)
Ki (nM)
b
c
d
e
f
R
D2
D3
D2/D3
σ1
σ2
7
8
9
10
11
12
benzyl
9.7 ( 2.3
19 ( 11
5.9 ( 1.8
1.8 ( 0.4
132 ( 22
5.8 ( 3.6
1.0 ( 0.5
2.5 ( 1.0
0.8 ( 0.3
0.2 ( 0.1
12 ( 5
9.7
7.7
7.4
9.0
11
3.2 ( 0.4
3.6 ( 0.2
5.8 ( 0.2
4.8 ( 0.6
400 ( 2
28 ( 3
42 ( 0.4
27 ( 3
cyclopentyl
cyclohexyl
cycloheptyl
bicyclo[3.3.1]nonan-9-yl
2-adamantyl
25 ( 2
17 ( 0.4
137 ( 2
70 ( 10
0.4 ( 0.1
14.5
a-f See Table 1.
Ta ble 3. Dopamine D2 and D3 Receptor Binding Profiles of (R)-N-(1-Alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides
a
a
Ki (nM)
Ki (nM)
b
c
d
e
f
R
D2
D3
D2/D3
σ1
σ2
13
14
15
16
17
18
benzyl
12.0 ( 4.7
283 ( 21
74 ( 13
19 ( 7
75 ( 22
62 ( 19
1.6 ( 0.4
75 ( 32
5.7 ( 2.8
2.9 ( 1.8
13.2 ( 4.3
13.0 ( 6.6
7.5
3.8
13
6.7
5.7
4.8
5.9 ( 0.5
0.7 ( 0.03
1.2 ( 0.1
1.7 ( 0.2
6.2 ( 0.2
6.2 ( 0.1
20.8 ( 2.6
15.3 ( 0.6
9.8 ( 1.4
10.0 ( 2.8
279 ( 8
cyclopentyl
cyclohexyl
cycloheptyl
bicyclo[3.3.1]nonan-9-yl
2-adamantyl
21.4 ( 1.1
a-f See Table 1.
compounds at the D2 and D3 dopamine receptor sub-
types. The binding data for the (S) series is shown in
Table 2, and data for the (R) series are shown in Table
3. The results in both Tables 2 and 3 indicated that the
(S)- and the (R)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-
methoxy-2-naphthamide analogues demonstrated a 4-
to 15-fold selectivity for D3 compared to the selectivity
for D2 dopamine receptors. The benzyl (compounds 7
and 13) and the bicyclo[3.3.1]nonan-9-yl (compounds 11
and 17) substituted analogues had similar affinity and
selectivity for dopamine D2 and D3 receptors. When
compared to the corresponding (R)-series analogues
(Table 3), the remaining (S)-N-(1-alkylpyrrolidin-3-yl)-
4-bromo-1-methoxy-2-naphthamide analogues (Table 2)
were found (a) to bind with higher affinity at both D2
and D3 receptors and (b) to have higher selectivity for
D3 receptors than the (R)-series analogues. This obser-
vation is consistent with the results reported by Ohmori
and co-workers.25
in the (S) series (12) and (b) moderate affinity at D2 and
D3 receptors with a good D3 selectivity in the (R) series
(18).
While the size of the alkylpyrrolidin-3-yl moiety for
the (R)- and the (S)-series compounds clearly influenced
affinity at D2 and D3 dopamine receptor, it seems to
have less effect on the affinity at σ receptors. The
affinity at σ receptors was found to be higher for the
(R) series than for the (S) series for the majority of
compounds in these series (Tables 2 and 3). Of the (R)-
and the (S)-alkylpyrrolidin-3-yl derivatives, compound
12 had the most pharmacologically desirable properties
because it bound D3 receptors with nanomolar affinity
(Ki ) 0.4 nM) and was 15-fold selective at D3 compared
to the selectivity at D2 receptors. In addition, compound
12 was found to be 70- to 175-fold selective at D3
receptors compared to the selectivity of the σ receptor
subtypes.
The in vitro σ receptor binding results indicated that
the (S)- and (R)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-
methoxy-2-naphthamide analogues bound with high
affinity for σ1 receptors (except for 11) and moderate to
low affinity for σ2 receptors. As a result, many of these
compounds (Tables 2 and 3) were found to be selective
for both D3 and σ1 receptors. For example, compound
17 had a Ki value of 13 nM at D3 receptors and a 6-fold
selectivity for D3 versus D2 receptors. Compound 17 had
a Ki value of 6 nM at σ1 receptors with a 45-fold
selectivity for σ1 versus σ2 receptors.
The (S)-series compounds 8-10 and the (R)-series
compounds 14-16 both demonstrated an increased
affinity for both D2 and D3 receptors as a function of
increased ring size in the order Ki(cyclopentyl) > Ki(cyclohexyl)
> Ki(cycloheptyl). Although the bicyclo[3.3.1]nonan-9-yl
derivatives (11 and 17) had a significantly lowered
affinity for both D2 and D3 receptors, they maintained
a D3 receptor selectivity comparable to corresponding
cycloheptyl analogues (10 and 16, respectively). Com-
pounds with the 2-adamantyl moiety had (a) high
affinity at D2 and D3 receptors with good D3 selectivity
Tables 4 and 5 contain the in vitro binding results
for (S)- and (R)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-

1820 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Huang et al.
Ta ble 4. Dopamine D2 and D3 Receptor Binding Profiles of (S)-N-(1-Alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides
a
a
Ki (nM)
Ki (nM)
b
c
d
e
f
R
D2
D3
D2/D3
σ1
σ2
19
20
21
22
23
24
25
benzyl
151 ( 52
11.8 ( 1.5
59 ( 8
14.6 ( 3.6
1.9 ( 0.8
52 ( 11
10.3
6.2
1.1
1.3
1.6
3.4
4.4
56 ( 6
222 ( 3
152 ( 13
51 ( 2
147 ( 10
44 ( 0.1
267 ( 9
141 ( 13
cyclobutyl
cyclopentyl
cyclohexyl
cycloheptyl
bicyclo[3.3.1]nonan-9-yl
2-adamantyl
4.0 ( 0.7
2.5 ( 0.1
57 ( 4.5
442 ( 36
80 ( 11
334 ( 89
50 ( 11
12.7 ( 0.4
16.7 ( 1.6
23.4 ( 0.1
26 ( 5.1
300 ( 28
7.5 ( 1.6
68 ( 10
a-f See Table 1.
Ta ble 5. Dopamine D2 and D3 Receptor Binding Profiles of (R)-N-(1-Alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides
a
a
Ki (nM)
Ki (nM)
b
c
d
e
f
R
D2
D3
D2/D3
σ1
σ2
26
27
28
29
30
31
benzyl
cyclobutyl
cyclopentyl
cyclohexyl
cycloheptyl
2-adamantyl
11.4 ( 8.6
277 ( 67
157 ( 86.
58 ( 24
1.4 ( 0.7
90 ( 16
30 ( 9
3.2 ( 1.1
2.4 ( 1.1
2.6 ( 0.3
8
3
5
18.4
26
8.8
230 ( 5
48.( 2
207 ( 23
95 ( 2
31 ( 7
35 ( 5
20.7 ( 1.7
59 ( 3.3
375 ( 11
25 ( 1
63 ( 26
57 ( 9
22.9 ( 3.8
317 ( 12
a-f See Table 1.
1-methoxy-2-naphthamides. The compounds in this
series are structurally similar to nafadotride (Chart 1),
which was reported to be 10-fold-selective for D3 recep-
tors compared to the selectivity for the D2 dopamine
receptor subtype.34 Except for the cyclobutyl (20 versus
27) and cyclopentyl (21 versus 28) substituted ana-
logues, the (R) isomers (Table 5) were found to bind with
higher affinity at D3 receptors than the corresponding
(S)-isomers (Table 4). The size of the alkyl moiety for
the (R)- and the (S)-pyrrolidinylmethyl series of com-
pounds influenced the affinity of the compounds at D2
and D3 dopamine receptors, but the size influenced the
affinity in opposite directions. For the (S)-pyrrolidinyl-
methyl derivatives, increasing the size of the cycloalkyl
group from a cyclobutyl to a cyclohexyl group resulted
in a decrease in affinity at both D2 and D3 dopamine
receptors and a loss of D3 receptor selectivity (Table 4).
In contrast, a similar increase in the size of the
cycloalkyl group in the (R) series of compounds resulted
in an increase in affinity at D2-like dopamine receptors,
with increasing selectivity at the D3 receptor compared
to that at the D2 dopamine receptor subtype. Conse-
quently, the cyclohexyl- and the cycloheptyl-substituted
(R) isomers, compounds 29 and 30, exhibited an 18-fold
and 26-fold selectivity for D3 receptors, respectively.
The σ receptor binding results revealed that the (S)
isomers (Table 4) had a generally higher affinity at σ1
than at σ2 receptors, whereas the (R) isomers (Table 5)
showed almost identical affinity at both σ1 and σ2
receptors. The cyclobutyl-substituted (S) isomer, com-
pound 20, had high affinity for both D3 and σ1 receptors,
a moderate affinity for D2, and a low affinity for σ2
receptors. This analogue displayed a 6-fold selectivity
for D3 versus D2 receptors and a 38-fold selectivity for
σ1 versus σ2 receptors.
The final two naphthamides prepared for this study,
compounds 32 and 33, have a 9-azabicyclo[3.3.1]nonan-
3â-yl moiety (Table 6) as the central ring. The affinities
of compounds 32 and 33 at D2 and D3 receptors were
significantly decreased in comparison to the correspond-
ing 9-benzyl-substituted analogue, 37 (Ki ) 0.20 and
0.04 nM for D2 and D3 receptors, respectively).23 How-
ever, compounds 32 and 33 showed a moderate selectiv-
ity for D3 receptors, whereas the corresponding 1-alkyl-
piperidin-4-yl analogues, 3 and 4, had a moderate
selectivity for the D2 receptor (Table 1). The relatively
low dopamine receptor affinity of compounds 2-6, 32,
and 33 indicates that the N-cycloalkyl is not favorable
for either D2 or D3 receptor binding for the piperidin-
4-yl and 9-azabicyclononan-3â-yl analogues, whereas
the N-benzyl moiety is beneficial for both D2 and D3
receptor binding. The high affinity of 32 and 33 for σ2
receptors versus σ1, D2, and D3 receptors indicates that
these analogues may be useful lead compounds for
developing σ2-selective ligands.
In conclusion, a series of naphthamides have been
synthesized and assessed for their binding affinity at
D2 and D3 dopamine and the σ1 and σ2 receptor
subtypes. This research extends previous efforts to
explore the fundamental structure-activity relation-
ships of benzamide-related analogues as potential selec-
tive antagonists for the D3 dopamine receptor sub-

Naphthamides as Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1821
Ta ble 6. Dopamine D2 and D3 Receptor Binding Profiles of
N-(9-Alkyl-9-azabicyclo[3.3.1]nonan-3â-yl)-4-bromo-1-methoxy-2-naphthamides
a
a
Ki (nM)
Ki (nM)
b
c
d
e
f
R
D2
D3
D2/D3
σ1
σ2
32
cyclohexyl
cycloheptyl
benzyl
150 ( 42
152 ( 14
48 ( 17
41 ( 16
3
69 ( 4
96 ( 3
74 ( 3
1.5 ( 0.2
>1000
4.8 ( 0.6
7.9 ( 1.2
250 ( 5
17 ( 0.6
419 ( 32
33
3.7
5.0
0.16
1.2
37g
0.20 ( 0.08
7.6 ( 2.0
0.04 ( 0.01
47 ( 19
haloperidol
IABNh
0.05 ( 0.01i
0.04 ( 0.004i
h
a-f See Table 1. g Reference 23. N-(9-benzyl-9-azabicyclo[3.3.1]nonan-3â-yl)-2,3-dimethoxy-5-iodobenzamide. i Kd values from Scatchard
studies.
type.21-23 In this report the steric effects of the N-
substituent naphthamides on the binding affinity for D2
and D3 dopamine receptors have been investigated.
Naphthamides having the N-(1-cycloalkylpiperidin-4-
yl) moiety were found to bind with low affinity at both
D2 and D3 receptors, while most of the compounds
having either the (S)- or (R)-N-(1-cycloalkylpyrrolidin-
3-yl), or the (S)- or (R)-N-(1-cycloalkyl-2-pyrrolidinylm-
ethyl) moiety had moderate to high affinity for D3
receptors and moderate to low affinity at D2 receptors.
The σ receptor binding results indicated that the major-
ity of the naphthamide analogues had moderate to high
affinity for the σ1 and σ2 receptor subtypes. The piperi-
dine derivatives (2-5) were potent σ1 and σ2 nonselec-
tive ligands, with lower affinity at D2-like receptors. The
pyrrolidine-containing derivatives (7-10 and 12-18)
were potent σ1 receptor selective ligands with varying
affinity at D2-like dopamine receptors. The pyrrolidi-
nylmethyl derivatives (19-31) were either slightly σ1
selective or nonselective at σ1 and σ2 receptors with
varying affinity at D2-like dopamine receptors. The
9-cycloalkyl-9-azabicyclo[3.3.1]nonane derivatives (32,
33) were found to be σ2 receptor selective ligands. A
number of the analogues described above showed high
affinity and moderate selectivity for D3 versus D2
receptors, as well as high affinity and high selectivity
for σ1 versus σ2 receptors. Preliminary studies using the
35S-GTPγS binding assay in rat striatal tissue indicate
that a number of the compounds described above
function as antagonists of the D2-like receptors (unpub-
lished data). Therefore, the pharmacologic properties of
the compounds prepared for this report suggest that
naphthamide-type drugs are potential pharmacothera-
peutic agents for the treatment of neuropsychiatric
disorders or for the rehabilitation of patients who abuse
psychostimulants.
tiplicity of NMR signals: s ) singlet, d ) doublet, t ) triplet,
q ) quartet, m ) multiplet, dd ) double doublet, dt ) double
triplet, dq ) double quartet, br ) broad. All starting materials
and solvents were purchased from Aldrich, Fisher, or Lan-
caster and were used without further purification.
4-Br om o-1-m eth oxy-2-n aph th oyl Ch lor ide. Bromine was
added (31.96 g, 0.2 mol) to a solution of 1-hydroxy-2-naphthoic
acid (37.64 g, 0.2 mol) in acetic acid (500 mL). The mixture
was stirred at room temperature overnight. The solid was
filtered and dried to give 4-bromo-1-hydroxy-2-naphthoic acid
(53.2 g, 99%), which was used for the next reaction without
further purification. 1H NMR (acetone-d6): δ 6.37-6.40 (d, 1H),
6.10-6.13 (d, 1H), 6.06 (s, 1H), 5.78-5.84 (dt, 1H), 5.63-5.69
(dt, 1H).
A mixture of 4-bromo-1-hydroxy-2-naphthoic acid (51.0 g,
0.19 mol), dimethyl sulfate (48.17 g, 0.38 mol), potassium
carbonate (52.78 g, 0.38 mol), and acetone (500 mL) was
refluxed overnight. The solid was filtered, and the solution was
condensed to give a solid residue, which was recrystallized
from ethyl acetate/hexane to afford methyl 4-bromo-1-methoxy-
1
2-naphthoate (54.0 g, 96%); mp 84-85 °C. H NMR (CDCl3):
δ 8.29-8.32 (d, 1H), 8.20-8.23 (d, 1H), 8.19 (s, 1H), 7.68-
7.74 (dt, 1H), 7.60-7.66 (dt, 1H), 4.06 (s, 3H), 3.99 (s, 3H).
NaOH (40%, 20 mL) was added slowly to a solution of
methyl 4-bromo-1-methoxy-2-naphthoate (54 g, 0.18 mol) in
methanol (500 mL) and refluxed for 3 h. The methanol was
removed, and the residue was added to an ice-cold 6 N HCl
solution to give pH e 2. The solid was filtered, dried, and
recrystallized from ethyl acetate to give 4-bromo-1-methoxy-
2-naphthoic acid (46.3 g, 90%); mp 180-181 °C. 1H NMR
(CDCl3): δ 8.39 (s, 1H), 8.23-8.30 (q, 2H), 7.74-7.80 (dt, 1H),
7.65-7.71 (dt, 1H), 4.15 (s, 3H).
Thionyl chloride (33.91 g, 0.28 mol) was added to a solution
of 4-bromo-1-methoxy-2-naphthoic acid (40.0 g, 0.14 mol) in
benzene (200 mL). After the mixture was refluxed overnight,
the solvent was removed and the residue was recrystallized
from ethyl acetate/hexane to give 4-bromo-1-methoxy-2-naph-
thoyl chloride (39.05 g, 92%); mp 99-100 °C. 1H NMR
(CDCl3): δ 8.34 (s, 1H), 8.30-8.33 (d, 1H), 8.23-8.26 (d, 1H),
7.76-7.82 (dt. 1H), 7.65-7.71 (dt, 1H), 4.06 (s, 3H).
1-Ben zyl-4-t r iflu or oa cet a m id op ip er id in e (Ia ). Tri-
fluoroacetic anhydride (12.6 g, 60 mmol) and 5 mL of triethyl-
amine was added to a solution of 4-amino-1-benzylpiperidine
(9.5 g, 50 mmol) in dry dichloromethane (200 mL) under ice.
After the mixture was stirred at room temperature for 12 h,
the solvent was removed under vacuo and the residue was
dissolved in ethyl acetate, washed with aqueous NaHCO3 and
water, and dried over Na2SO4. The solvent was removed, and
the product was recrystallized from ethyl acetate to give Ia
(13.5 g, 94%); mp 110-111 °C. 1H NMR (free amine in
CDCl3): δ 7.29-7.38 (m, 5H), 6.55-6.62 (d, 1H), 3.87-3.96
(m, 1H), 3.69 (s, 2H), 3.02-3.06 (d, 2H), 2.27-2.36 (dt, 2H),
1.98-2.01 (m, 2H), 1.67-1.81 (dq, 2H).
Exp er im en ta l Section
Ch em istr y. Melting points were measured on a Fisher-
J ohns melting point apparatus and are uncorrected. Elemental
analyses were performed by Atlantic Microlab, Inc., Norcross,
GA. Where molecular formulas were indicated, analyses were
found to be within 0.4% of the theoretical values unless
1
otherwise noted. H NMR spectra were recorded at 300 MHz
on a Bruker AVANCE300 spectrometer. All 1HNMR spectra
were obtained in either CDCl3 or DMSO-d6, and results were
recorded as parts per million (ppm) downfield to tetramethyl-
silane (TMS). The following abbreviations are used for mul-

1822 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Huang et al.
Gen er a l Meth od s for P r ep a r a tion of N-(1-Alk ylp ip er i-
d in -4-yl)-4-br om o-1-m eth oxy-2-n a p h th a m id e (2-6). Com-
pounds 2-6 were prepared by a reductive alkylation of Ia with
a cycloketone under catalytical hydrogenation and followed by
cleavage of the trifluoroacetyl moiety and condensation with
4-bromo-1-methoxy-2-naphthoyl chloride.
added to a solution of (R)-1-benzyl-3-pyrrolidinol (5.0 g, 28.2
mmol) and triethylamine (5.71 g, 56.4 mmol) in dry THF (50
mL) at -10 °C. The mixture was stirred at -10 to 0 °C for 4
h and then stirred at room temperature overnight. The solvent
was removed, and the residue was purified by a silica gel
column with CHCl3/ethyl acetate (9:1) as the elutant to give
(R)-1-benzyl-3-pyrrolidinol methanesulfate as an oil (6.96 g,
96.7%). 1H NMR (CDCl3): δ 7.23-7.35 (m, 5H), 5.15-5.22 (m,
1H), 3.59-3.71 (q, 2H), 2.99 (s, 3H), 2.76-2.86 (m, 3H), 2.46-
2.54 (m, 1H), 2.27-2.35 (m, 1H), 2.07-2.11 (m, 1H).
N-(1-Cyclop en t ylp ip er id in -4-yl)-4-b r om o-1-m et h oxy-
n a p h th a m id e (2). A mixture of Ia (0.57 g, 2 mmol), cyclo-
pentanone (0.5 g, 5.9 mmol), and 20% palladium hydroxide
on carbon (25 mg) and 10% palladium on activated carbon (25
mg) in methanol (100 mL) was hydrogenated under 50 psi for
12 h at room temperature. The catalyst was removed by
filtration. The filtrate was concentrated, and ammonium
hydroxide (30%, 20 mL) and methanol (50 mL) was then
added. This mixture was refluxed for 4 h and then gradually
cooled to room temperature. The mixture was concentrated
in vacuo, and the residue was dissolved in 2 N HCl (25 mL)
and extracted with ethyl acetate (3 × 30 mL). The aqueous
phase was separated and adjusted to pH g 10 with 6 N NaOH.
The product was extracted with dichloromethane (3 × 20 mL)
and dried over Na2SO4. The Na2SO4 was removed by filtration.
4-Bromo-1-methoxy-2-naphthoyl chloride (0.6 g, 2 mmol) and
triethylamine (0.5 mL) was added to the filtrate, and the
mixture was stirred overnight. The solution was concentrated.
The residue was extracted with dichloromethane (3 × 30 mL)
and dried over Na2SO4. The product was purified by a silica
gel column with CHCl3/ethanol (9.5:0.5) as the elutant and
recrystallized from ethyl acetate/hexane to give N-(1-cyclo-
pentylpiperidin-4-yl)-4-bromo-1-methoxy-2-naphthamide, 2 (0.48
g, 56%); mp 171-173 °C. 1H NMR (CDCl3): δ 8.41 (s, 1H),
8.23-8.26 (dd, 1H), 8.15-8.18 (dd, 1H), 7.84-7.87 (d, 1H, CO-
NH), 7.66-7.72 (dt, 1H), 7.60-7.66 (dt, 1H), 4.05-4.12 (m,
1H), 3.97 (s, 3H, OCH3), 2.99-3.03 (d, 2H), 2.44-2.59 (m, 1H),
2.09-2.48 (m, 2H), 1.86-1.95 (m, 2H), 1.48-1.63 (m, 10H).
Analysis results for (C22H27N2O2Br) C, H, N are in Supporting
Information.
The above oil (6.96 g, 27.3 mmol) was dissolved in dry DMF
(50 mL). Sodium azide (6.5 g, 100 mmol) was added, and the
mixture was heated at 80 °C overnight. The mixture was
poured into ice-cold water (150 mL), extracted with dichloro-
methane (3 × 30 mL), and dried over Na2SO4. The solvent was
removed, and the residue was dissolved in dry THF (100 mL).
Lithium aluminum hydride (1.04 g, 27.4 mmol) was slowly
added, and the mixture was refluxed for 6 h and then cooled
to room temperature. Water (2 mL) and 2 N NaOH (2 mL)
was added to the mixture dropwise. The solid was removed
by filtration, and the solution was concentrated in vacuo. The
residue was purified by a silica gel column with CHCl3/ethanol
(8:2) as the elutant to give (R)-3-amino-1-benzylpyrrolidine
1
(3.79 g, 79%). H NMR (CDCl3): δ 7.24-7.32 (m, 5H), 3.55-
3.65 (q, 2H), 3.48-3.52 (m, 1H), 2.68-2.73 (m, 2H), 2.45-2.48
(m, 1H), 2.31-2.35 (m, 1H), 2.16-2.22 (m, 1H), 1.45-1.52 (m,
1H).
A solution of containing (R)-3-amino-1-benzylpyrrolidine
(3.50 g, 20 mmol) and di-tert-butyl dicarbonate (4.34 g, 20
mmol) in dichloromethane (30 mL) was stirred at room
temperature overnight. The mixture was washed with 1 N
NaOH (30 mL) and then with water and dried over Na2SO4.
The solvent was removed, and the residue was purified by a
silica gel column with CHCl3/ethanol (9:1) as the elutant to
give IIa (4.27 g, 77%); mp 69-70 °C. 1H NMR (CDCl3): δ 7.21-
7.34 (m, 5H), 4.16 (m, 1H), 3.58 (s, 2H), 2.77-2.82 (m, 1H),
2.43-2.63 (m, 2H), 2.19-2.31 (m, 2H), 1.70-1.75 (m, 1H),
1.56-1.62 (m, 1H), 1.43 (s, 9H). Analysis results for
(C16H24N2O2) C, H, N are in Supporting Information.
(R)-1-Benzyl-3-(tert-butoxycarbonylamino)pyrrolidine (IIb),
(S)-N-(1-benzyl-2-pyrrolidinylmethyl)-tert-butoxycarbamide (IIc),
and (R)-N-(1-benzyl-2-pyrrolidinylmethyl)-tert-butoxycarb-
amide (IId ) were prepared with methods similar to those
described above and were used directly in subsequent reac-
tions.
N-(1-Cycloh exylp ip er id in -4-yl)-4-br om o-1-m eth oxy-2-
n a p h th a m id e (3). Yield of 45% from Ia (three steps); mp
1
167-168 °C. H NMR (CDCl3): δ 8.41 (s, 1H), 8.23-8.26 (dd,
1H), 8.15-8.18 (dd, 1H), 7.83-7.86 (d, 1H, CO-NH), 7.66-
7.72 (dt, 1H), 7.60-7.66 (dt, 1H), 4.07-4.14 (m, 1H), 3.97 (s,
3H, OCH3), 2.95-3.00 (d, 2H), 2.41-2.54 (m, 1H), 2.09-2.18
(m, 2H), 1.80-1.96 (m, 4H), 1.57-1.64 (m, 6H), 1.18-1.29 (m,
4H). Analysis results for (C23H29N2O2Br) C, H, N are in
Supporting Information.
N-(1-Cycloh ep tylp ip er id in -4-yl)-4-br om o-1-m eth oxy-2-
n a p h th a m id e (4). Yield of 27% from Ia (three steps); mp
152-153 °C. H NMR (CDCl3): δ 8.41 (s, 1H), 8.23-8.26 (dd,
Gen er a l Meth od s for th e P r ep a r a tion of Na p h th -
a m id es 1, 7, 13, 19, 26, 32, a n d 33. These compounds were
obtained directly by condensing the amines and the 4-bromo-
1-methoxy-2-naphthoyl chloride at room temperature.
N-(1-Ben zylpiper idin -4-yl)-4-br om o-1-m eth oxy-2-n aph -
th a m id e (1). Yield of 93% from 1-benzyl-4-aminopiperidine;
1
1H), 8.15-8.18 (dd, 1H), 7.83-7.86 (d, 1H, CO-NH), 7.66-
7.72 (dt, 1H), 7.60-7.66 (dt, 1H), 4.03-4.12 (m, 1H), 3.97 (s,
3H, OCH3), 2.82-2.86 (d, 2H), 2.55-2.65 (m, 1H), 2.43-2.51
(m, 2H), 1.82-1.88 (m, 2H), 1.44-1.67 (m, 12H). Analysis
results for (C24H31N2O2Br) C, H, N are in Supporting Informa-
tion.
N-(1-(Bicyclo[3.3.1]n on a n -9-yl)p ip er id in -4-yl)-4-br om o-
1-m eth oxy-2-n a p h th a m id e (5). Yield of 31% from Ia (three
steps); mp 169-171 °C. 1H NMR (CDCl3): δ 8.41 (s, 1H), 8.23-
8.26 (dd, 1H), 8.16-8.19 (dd, 1H), 7.85-7.88 (d, 1H, CO-NH),
7.66-7.72 (dt, 1H), 7.60-7.66 (dt, 1H), 4.04-4.15 (m, 1H), 3.97
(s, 3H, OCH3), 2.91-2.95 (d, 2H), 2.78-2.87 (m, 1H), 2.37-
2.44 (m, 2H), 1.62-1.73 (m, 6H), 1.22-1.27 (m, 2H), 1.09-
1.11 (d, 8H). Analysis results for (C26H33N2O2Br) C, H, N are
in Supporting Information.
1
mp 145-146 °C. H NMR (CDCl3): δ 8.40 (s, 1H), 8.23-8.26
(dd, 1H), 8.15-8.18 (dd, 1H), 7.82-7.85 (d, 1H, CO-NH),
7.66-7.72 (dt, 1H), 7.60-7.66 (dt, 1H), 7.26-7.34 (m, 5H),
4.05-4.17 (m, 1H), 3.95 (s, 3H, OCH3), 3.56 (s, 2H), 2.84-2.88
(d, 2H), 2.21-2.28 (dt, 2H), 2.04-2.09 (m, 2H), 1.60-1.72 (m,
2H). Analysis results for (C24H25N2O2Br) C, H, N are in
Supporting Information.
(S)-N-(1-Ben zylp yr r olid in -3-yl)-4-br om o-1-m eth oxy-2-
n a p h th a m id e (7). Yield of 65% from (S)-1-benzyl-3-aminopy-
rrolidine; mp 162-164 °C (oxalate). 1H NMR (free amine in
CDCl3): δ 8.39 (s, 1H), 8.22-8.25 (dd, 2H), 8.17-8.20 (dd, 2H),
7.66-7.72 (dt, 1H), 7.60-7.66 (dt, 1H), 7.22-7.39 (m, 5H),
4.68-4.76 (m, 1H), 3.92 (s, 3H, OCH3), 3.60-3.73 (q, 2H),
2.64-2.76 (m, 2H), 2.33-2.44 (m, 2H), 1.72-1.84 (m, 2H).
Analysis results for (C25H25N2O6Br) C, H, N are in Supporting
Information.
(R)-N-(1-Ben zylp yr r olid in -3-yl)-4-br om o-1-m eth oxy-2-
n a p h th a m id e (13). Yield of 49% from (R)-1-benzyl-3-amino-
pyrrolidine; mp 150-152 °C (oxalate). 1H NMR (free amine in
CDCl3): δ 8.40 (s, 1H), 8.22-8.25 (dd, 2H), 8.17-8.20 (dd, 2H),
7.66-7.72 (dt, 1H), 7.60-7.66 (dt, 1H), 7.23-7.39 (m, 5H),
4.69-4.76 (m, 1H), 3.92 (s, 3H, OCH3), 3.60-3.71 (q, 2H),
2.64-2.76 (m, 2H), 2.33-2.46 (m, 2H), 1.71-1.84 (m, 2H).
N-(1-(Ad a m a n ta n -2-yl)p ip er id in -4-yl)-4-br om o-1-m eth -
oxy-2-n a p h th a m id e (6). Yield of 21% from Ia (three steps);
1
mp 189-190 °C. H NMR (CDCl3): δ 8.41 (s, 1H), 8.23-8.26
(dd, 1H), 8.16-8.19 (dd, 1H), 7.83-7.85 (d, 1H, CO-NH),
7.66-7.72 (dt, 1H), 7.60-7.66 (dt, 1H), 4.03-4.13 (m, 1H), 3.99
(s, 3H, OCH3), 2.94-3.02 (d, 2H), 2.065-2.09 (m, 9H), 1.79-
1.89 (m, 4H), 1.59-1.71 (m, 6H), 1.36-1.44 (d, 2H). Analysis
results for (C27H33N2O2Br) C, H, N are in Supporting Informa-
tion.
(S )-1-Be n zyl-3-(t er t -b u t oxyca r b on yla m in o)p yr r oli-
d in e (IIa ). Methanesulfonyl chloride (3.88 g, 33.87 mmol) was

Naphthamides as Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1823
Analysis results for (C25H25N2O6Br) C, H, N are in Supporting
Information.
the elutant to give a free amine product, which was converted
into an oxalate salt, using oxalic acid (2 equiv) in ethyl acetate.
(S)-N-(1-Cyclop en tylp yr r olid in -3-yl)-4-br om o-1-m eth -
oxy-2-n a p h th a m id e (8). Yield of 37% from IIa (three steps);
mp 70-73 °C (oxalate). 1H NMR (free amine in CDCl3): δ 8.40
(s, 1H), 8.22-8.25 (dd, 1H), 8.16-8.19 (dd, 2H), 7.66-7.72 (dt,
1H), 7.59-7.65 (dt, 1H), 4.71-4.74 (m, 1H), 3.99 (s, 3H, OCH3),
2.94-2.97 (m, 1H), 2.77-2.83 (m, 2H), 2.33-2.54 (m, 4H),
1.69-1.85 (m, 8H). Analysis results for (C23H27N2O6Br‚1H2O)
C, H, N are in Supporting Information.
(S)-N-(1-Ben zyl-2-pyr r olidin ylm eth yl)-4-br om o-1-m eth -
oxy-2-n a p h th a m id e (19). Yield of 57% from (S)-1-benzyl-2-
1
pyrrolidinylmethylamine; mp 112-114 °C (oxalate). H NMR
(free amine in CDCl3): δ 8.45 (s, 1H), 8.34-8.40 (b, 1H, CO-
NH), 8.19-8.27 (m, 2H), 7.64-7.70 (m, 2H), 7.21-7.39 (m, 5H),
3.97 (s, 3H, OCH3), 3.45-3.55 (m, 2H), 2.75-2.85 (m, 2H),
2.20-2.30 (m, 1H), 1.65-1.80 (m, 6H). Analysis results for
(C26H27N2O6Br) C, H, N are in Supporting Information.
(S)-N-(1-Cycloh exylpyr r olidin -3-yl)-4-br om o-1-m eth oxy-
2-n a p h th a m id e (9). Yield of 29% from IIa (three steps); mp
66-68 °C (oxalate). 1H NMR (free amine in CDCl3): δ 8.40 (s,
1H), 8.23-8.26 (dd, 2H), 8.16-8.19 (dd, 1H), 7.66-7.72 (dt,
1H), 7.60-7.65 (dt, 1H), 4.71-4.74 (m, 1H), 3.99 (s, 3H, OCH3),
3.00-3.10 (m, 1H), 2.85-2.93 (m, 2H), 2.32-2.52 (m, 2H),
1.65-1.75 (m, 2H), 1.22-1.28 (m, 10H). Analysis results for
(C24H29N2O6Br‚2H2O) C, H, N are in Supporting Information.
(S)-N-(1-Cycloh ep tylp yr r olid in -3-yl)-4-br om o-1-m eth -
oxy-2-n a p h th a m id e (10). Yield of 63% from IIa (three steps);
mp 83-85 °C (oxalate). 1H NMR (free amine in CDCl3): δ 8.39
(s, 1H), 8.22-8.25 (dd, 2H), 8.16-8.19 (dd, 1H), 7.66-7.71 (dt,
1H), 7.60-7.65 (dt, 1H), 4.71-4.76 (m, 1H), 3.99 (s, 3H, OCH3),
3.04-3.12 (m, 1H), 2.85-2.93 (m, 2H), 2.48-2.56 (m, 2H),
2.30-2.40 (m, 2H), 1.82-1.92 (m, 4H), 1.35-1.70 (m, 8H).
Analysis results for (C25H31N2O6Br‚1H2O) C, H, N are in
Supporting Information.
(S)-N-(1-(Bicyclo[3.3.1]n on a n -9-yl)p yr r olid in -3-yl)-4-
br om o-1-m eth oxy-2-n a p h th a m id e (11). Yield of 63% from
IIa (three steps); mp 73-75 °C (oxalate); 1H NMR (free amine
in CDCl3): δ 8.39 (s, 1H), 8.22-8.25 (dd, 2H), 8.15-8.19 (dd,
1H), 7.66-7.71 (dt, 1H), 7.59-7.65 (dt, 1H), 4.73-4.79 (m, 1H),
3.99 (s, 3H, OCH3), 3.00-3.10 (m, 1H), 2.85-2.90 (m, 2H),
2.35-2.53 (m, 4H), 1.80-1.90 (m, 4H), 1.13-1.18 (m, 10H).
Analysis results for (C27H33N2O6Br‚1/2H2O) C, H, N are in
Supporting Information.
(S)-N-(1-(2-Adam an tyl)pyr r olidin -3-yl)-4-br om o-1-m eth -
oxy-2-n a p h th a m id e (12). Yield of 35% from IIa (three steps);
mp 77-80 °C (oxalate). 1H NMR (free amine in CDCl3): δ 8.44
(s, 1H), 8.29-8.31 (d, 1H, CO-NH), 8.23-8.26 (dd, 1H), 8.17-
8.20 (dd, 1H), 7.66-7.71 (dt, 1H), 7.60-7.65 (dt, 1H), 4.68-
4.75 (m, 1H), 3.99 (s, 3H, OCH3), 3.00-3.08 (m, 1H), 2.50-
2.60 (m, 2H), 2.15-2.24 (m, 4H), 1.90-2.10 (m, 8H), 1.55-
1.65 (m, 4H), 1.45-1.53 (m, 2H). Analysis results for
(C28H33N2O6Br‚1.5H2O) C, H, N are in Supporting Information.
(R)-N-(1-Cyclop en tylp yr r olid in -3-yl)-4-br om o-1-m eth -
oxy-2-n a p h th a m id e (14). Yield of 24% from IIb (three steps);
mp 88-91 °C (oxalate). 1H NMR (free amine in CDCl3): δ 8.40
(s, 1H), 8.22-8.25 (dd, 1H), 8.16-8.19 (dd, 2H), 7.66-7.72 (dt,
1H), 7.60-7.65 (dt, 1H), 4.71-4.76 (m, 1H), 3.99 (s, 3H, OCH3),
2.96-2.99 (m, 1H), 2.78-2.96 (m, 2H), 2.33-2.55 (m, 4H),
1.70-1.82 (m, 8H). Analysis results for (C23H27N2O6Br‚1H2O)
C, H, N are in Supporting Information.
(R)-N-(1-Cycloh exylpyr r olidin -3-yl)-4-br om o-1-m eth oxy-
2-n a p h th a m id e (15). Yield of 50% from IIb (three steps); mp
75-78 °C (oxalate). 1H NMR (free amine in CDCl3): δ 8.40 (s,
1H), 8.22-8.25 (dd, 2H), 8.16-8.19 (dd, 1H), 7.66-7.72 (dt,
1H), 7.60-7.65 (dt, 1H), 4.64-4.74 (m, 1H), 3.98 (s, 3H, OCH3),
2.97-3.04 (m, 1H), 2.81-2.83 (m, 2H), 2.37-2.43 (m, 2H),
1.65-1.73 (m, 2H), 1.24-1.31 (m, 10H). Analysis results for
(C24H29N2O6Br‚1/2H2O) C, H, N are in Supporting Information.
(R)-N-(1-Cycloh ep tylp yr r olid in -3-yl)-4-br om o-1-m eth -
oxy-2-n a p h th a m id e (16). Yield of 39% from IIb (three steps);
mp 73-75 °C (oxalate). 1H NMR (free amine in CDCl3): δ 8.41
(s, 1H), 8.22-8.25 (dd, 2H), 8.17-8.20 (dd, 1H), 7.66-7.71 (dt,
1H), 7.60-7.66 (dt, 1H), 4.66-4.72 (m, 1H), 3.99 (s, 3H, OCH3),
2.95-3.03 (m, 1H), 2.79-2.81 (m, 2H), 2.29-2.48 (m, 4H),
1.24-1.84 (m, 12H). Analysis results for (C25H31N2O6Br‚1H2O)
C, H, N are in Supporting Information.
(R)-N-(1-Ben zyl-2-pyr r olidin ylm eth yl)-4-br om o-1-m eth -
oxy-2-n a p h th a m id e (26). Yield of 76% from (R)-1-benzyl-2-
pyrrolidinylmethylamine; mp 98-100 °C (oxalate). 1H NMR
(free amine in CDCl3): δ 8.45 (s, 1H), 8.36-8.46 (b, 1H, CO-
NH), 8.25-8.28 (m, 2H), 7.65-7.75 (m, 2H), 7.21-7.45 (m, 5H),
3.94 (s, 3H, OCH3), 3.50-3.55 (m, 2H), 2.70-2.80 (m, 2H),
2.20-2.30 (m, 1H), 1.78-1.82 (m, 6H). Analysis results for
(C26H27N2O6Br‚1H2O) C, H, N are in Supporting Information.
N-(9-Cycloh exyl-9-a za bicyclo[3.3.1]n on a n -3â-yl)-4-br o-
m o-1-m eth oxy-2-n a p h th a m id e (32). 3â-Amino-9-cyclohexyl-
9-azabicyclo[3.3.1]nonane was prepared in three steps. First,
a Mannich reaction of cyclohexylamine, glutaric dialdehyde,
and 1,3-acetonedicarboxylic acid was performed to give 9-cy-
clohexyl-9-azabicyclo[3.3.1]non-3-one, using the methods pre-
viously described.18 The product was then converted into an
oxime by reaction with hydroxylamine hydrochloride in re-
fluxing ethanol (50% yield). Finally, the oxime was reduced
using sodium in amyl alcohol to give 3â-amino-9-cyclohexyl-
9-azabicyclo[3.3.1]nonane in quantitative yield.
N-(9-Cyclohexyl-9-azabicyclo[3.3.1]nonan-3â-yl)-4-bromo-1-
methoxy-2-naphthamide was obtained in 74% yield from 3â-
amino-9-cyclohexyl-9-azabicyclo[3.3.1]nonane; mp 164-166 °C.
1H NMR (CDCl3): δ 8.40 (s, 1H), 8.25-8.28 (d, 1H), 8.18-
8.21 (d, 1H), 7.62-7.74 (m, 3H), 4.98-5.06 (m, 1H), 4.01 (s,
3H, OCH3), 3.36 (b, 2H), 3.09 (b, 1H), 1.28-2.20 (m, 20H).
Analysis results for (C26H33N2O2Br) C, H, N are in Supporting
Information.
N-(9-Cycloh eptyl-9-azabicyclo[3.3.1]n on an -3â-yl)-4-br o-
m o-1-m eth oxy-2-n a p h th a m id e (33). 3â-Amino-9-cyclohep-
tyl-9-azabicyclo[3.3.1]nonane was prepared with methods
similar to those described above.
N-(9-Cycloheptyl-9-azabicyclo[3.3.1]nonan-3â-yl)-4-bromo-1-
methoxy-2-naphthamide was obtained with a 64% yield from
3â-amino-9-cycloheptyl-9-azabicyclo[3.3.1]nonane; mp 169-
170 °C. 1H NMR (CDCl3): δ 8.38 (s, 1H), 8.22-8.25 (d, 1H),
8.15-8.18 (d, 1H), 7.59-7.71 (m, 3H), 4.94-5.04 (m, 1H), 3.98
(s, 3H, OCH3), 3.35 (s, 2H), 3.09 (m, 1H), 1.45-2.15 (m, 22H).
Analysis results for (C27H35N2O2Br) C, H, N are in Supporting
Information.
Gen er a l Meth od s for P r ep a r a tion of Na p h th a m id es
8-12, 14-18, 20-25, a n d 27-31. (S)-1-Benzyl-3-(tert-butoxy-
carbonylamino)pyrrolidine (IIa ), (R)-1-benzyl-3-(tert-butoxy-
carbonylamino)pyrrolidine (IIb), (S)-N-(1-benzyl-2-pyrrolidi-
nylmethyl)-tert-butoxycarbamide (IIc), or (R)-N-(1-benzyl-2-
pyrrolidinylmethyl)-tert-butoxycarbamide (IId ) was dissolved
in methanol (100 mL). Two equivalents of cycloketone, 5%
palladium hydroxide on carbon, and 5% palladium on activated
carbon was then added to the solution. After the mixture was
hydrogenated at 50 psi for 12 h, the catalyst was removed by
filtration and the solution was concentrated in vacuo. The
residue was dissolved in dichloromethane (30 mL), and tri-
fluoroacetic acid (5 mL) was added. The reaction mixture was
stirred at room temperature for 1 h, poured into ice-cold water,
and adjusted to give pH > 10 with 2 N NaOH. The filtrate
was extracted with dichloromethane (3 × 30 mL) and dried
over Na2SO4. After the Na2SO4 was removed by filtration,
4-bromo-1-methoxy-2-naphthoyl chloride and triethylamine (1
mL) were added to the filtrate and the reaction mixture was
stirred at room temperature overnight. The solvent was
removed in vacuo, and the residue was dissolved in dichloro-
methane, washed with 1 N NaOH and water and dried over
Na2SO4. The solvent was removed, and the residue was
purified by silica gel column with CHCl3/ethanol (9.5:0.5) as
(R)-N-(1-(Bicyclo[3.3.1]n on a n -9-yl)p yr r olid in -3-yl)-4-
br om o-1-m eth oxy-2-n a p h th a m id e (17). Yield of 30% from
IIb (three steps); mp 78-80 °C (oxalate). 1H NMR (free amine
in CDCl3): δ 8.44 (s, 1H), 8.30-8.33 (d, 1H, CO-NH), 8.22-
8.26 (dd, 1H), 8.17-8.20 (dd, 1H), 7.66-7.72 (dt, 1H), 7.60-

1824 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Huang et al.
7.65 (dt, 1H), 4.67-4.74 (m, 1H), 3.99 (s, 3H, OCH3), 3.00-
3.03 (m, 1H), 2.82-2.86 (m, 1H), 2.49-2.55 (m, 1H), 2.20-
2.40 (m, 4H), 1.44-2.04 (m, 16H). Analysis results for
(C27H33N2O6Br‚1.5H2O) C, H, N are in Supporting Information.
(R)-N-(1-(2-Adam an tyl)pyr r olidin -3-yl)-4-br om o-1-m eth -
oxy-2-n a p h th a m id e (18). Yield of 42% from IIb (three steps);
mp 86-88 °C (oxalate). 1H NMR (free amine in CDCl3): δ 8.44
(s, 1H), 8.29-8.31 (d, 1H, CO-NH), 8.23-8.26 (dd, 1H), 8.17-
8.20 (dd, 1H), 7.66-7.72 (dt, 1H), 7.60-7.65 (dt, 1H), 4.67-
4.75 (m, 1H), 3.99 (s, 3H, OCH3), 2.98-3.05 (m, 1H), 2.82-
2.86 (m, 1H), 2.50-2.56 (m, 1H), 2.20-2.38 (m, 6H), 1.70-
1.90 (m, 10H), 1.45-1.53 (m, 2H). Analysis results for
(C28H33N2O6Br‚1.5H2O) C, H, N are in Supporting Information.
(S)-N-(1-Cyclobu tyl-2-p yr r olid in ylm eth yl)-4-br om o-1-
m eth oxy-2-n a p h th a m id e (20). Yield of 25% from IIc (three
steps); mp 64-66 °C (oxalate). 1H NMR (free amine in
CDCl3): δ 8.45 (s, 1H), 8.32-8.40 (b, 1H, CO-NH), 8.23-8.26
(dd, 1H), 8.19-8.22 (dd, 1H), 7.66-7.72 (dt, 1H), 7.60-7.66
(dt, 1H), 4.35 (m, 1H), 4.04 (s, 3H), 4.02 (s, 3H, OCH3), 1.6-
2.8 (m, 16H). Analysis results for (C23H27N2O6Br‚2H2O) C, H,
N are in Supporting Information.
1.50-2.50 (m, 17H). Analysis results for (C24H29N2O6Br‚2H2O)
C, H, N are in Supporting Information.
(R)-N-(1-Cycloh exyl-2-p yr r olid in ylm eth yl)-4-br om o-1-
m eth oxy-2-n a p h th a m id e (29). Yield of 42% from IId (three
steps); mp 74-76 °C (oxalate). 1H NMR (free amine in
CDCl3): 8.50-8.53 (b, 1H, CO-NH), 8.46 (s, 1H), 8.19-8.25
(m, 2H), 7.62-7.70 (m, 2H), 4.34 (m, 1H), 4.02 (s, 3H, OCH3),
1.15-2.50 (m, 19H). Analysis results for (C25H31N2O6Br‚2H2O)
C, H, N are in Supporting Information.
(R)-N-(1-Cycloh ep tyl-2-p yr r olid in ylm eth yl)-4-br om o-
1-m eth oxy-2-n a p h th a m id e (30). Yield of 63% from IId
1
(three steps); mp 83-85 °C (oxalate). H NMR (free amine in
CDCl3): δ 8.53 (b, 1H, CO-NH), 8.46 (s, 1H), 8.19-8.26 (m,
2H), 7.61-7.70 (m, 2H), 4.35 (b, 1H), 4.02 (s, 3H, OCH3), 1.20-
2.30 (m, 21H). Analysis results for (C26H33N2O6Br‚2H2O) C,
H, N are in Supporting Information.
(R)-N-(1-(2-Adam an tyl)-2-pyr r olidin ylm eth yl)-4-br om o-
1-m eth oxy-2-n a p h th a m id e (31). Yield of 51% from IId
1
(three steps); mp 126-128 °C (oxalate). H NMR (free amine
in CDCl3): δ 8.44 (s, 1H), 8.29 (b, 1H, CO-NH), 8.19-8.24
(m, 2H), 7.60-7.71 (m, 2H), 4.03 (s, 3H, OCH3), 3.76-3.88 (m,
1H), 3.17-3.32 (m, 1H), 1.15-2.30 (m, 22H). Analysis results
for (C29H35N2O6Br‚2H2O) C, H, N are in Supporting Informa-
tion.
(S)-N-(1-Cyclop en t yl-2-p yr r olid in ylm et h yl)-4-br om o-
1-m eth oxy-2-n a p h th a m id e (21). Yield of 36% from IIc
1
(three steps); mp 66-68 °C (oxalate). H NMR (free amine in
In Vitr o Dop a m in e Recep tor Bin d in g Stu d ies. Radio-
labeled [125I]IABN was prepared using the peracetic acid
protocol previously described.35,36 The tributyltin precursor (50
µg) was combined with 5-10 mCi of [125I]NaI in 300 µL of 500
µM ammonium acetate, pH 4.0. Peracetic acid (50 µL of 0.32%
solution in water) was allowed to react for 2 min at room
temperature. Sodium metabisulfite (100 µL of 200 µg/mL
solution) was added to stop the reaction. After addition of
excess saturated sodium bicarbonate, the sample was extracted
with ethyl acetate to separate the free [125I]NaI from the
radiolabeled product. The organic phase was removed by
drying under N2, and the residue was dissolved in absolute
ethanol. The precursor and the labeled product were separated
on PRI reverse HPLC column using isocratic conditions with
an acetonitrile/ammonium phosphate (4 mM, pH 7.0) solvent
system (82:18).35- 36, 37
Rat dopamine D2-long and D3 receptors were expressed in
Sf9 cells infected using the appropriate recombinant baculo-
virus.36,38 Membrane homogenates were suspended in 50 mM
Tris-HCl/150 mM NaCl/1.0 mM EDTA buffer, pH 7.5, and
incubated with the radioligand at 37 °C for 60 min in the
presence or absence of competing ligands. For competition
experiments the radioligand concentration was approximately
equal to the Kd value of [125I]IABN and the concentration of
the competitive inhibitors ranged over 5 orders of magnitude
with two concentrations of inhibitor per decade. Nonspecific
binding was defined by the addition of 3 µM (+)-butaclamol.
Binding was terminated by the addition of cold wash buffer
(10 mM Tris-HCl/150 mM NaCl, pH 7.5 at 4 °C) and rapid
filtration over a glass-fiber filter (Schleicher and Schuell
No.30). Filters were washed with 10 mL of cold buffer, and
the bound radioactivity was measured using a Cobra II
Packard γ counter. The protein concentration was determined
using a BCA reagent (Pierce) with bovine serum albumin as
the protein standard.
CDCl3): δ 8.45 (s, 1H), 8.30-8.42 (b, 1H, CO-NH), 8.22-8.25
(d, 1H), 8.17-8.20 (d, 1H), 7.66-7.71 (dt, 1H), 7.60-7.65 (dt,
1H), 4.00 (s, 3H, OCH3), 3.70-3.85 (m, 1H), 2.95-3.10 (m, 1H),
2.50-2.65 (m, 2H), 1.60-1.80 (m, 14H). Analysis results for
(C24H29N2O6Br‚1.5H2O) C, H, N are in Supporting Information.
(S)-N-(1-Cycloh exyl-2-p yr r olid in ylm eth yl)-4-br om o-1-
m eth oxy-2-n a p h th a m id e (22). Yield of 30% from IIc (three
steps); mp 67-70 °C (oxalate). 1H NMR (free amine in
CDCl3): δ 8.51-8.53 (b, 1H, CO-NH), 8.46 (s, 1H), 8.18-8.25
(m, 2H), 7.59-7.70 (m, 2H), 4.26-4.34 (m, 1H), 4.01 (s, 3H,
OCH3), 1.10-2.70 (m, 19H). Analysis results for (C25H31N2O6-
Br‚1.5H2O) C, H, N are in Supporting Information.
(S)-N-(1-Cycloh ep t yl-2-p yr r olid in ylm et h yl)-4-br om o-
1-m eth oxy-2-n a p h th a m id e (23). Yield of 51% from IIc
1
(three steps); mp 70-73 °C (oxalate). H NMR (free amine in
CDCl3): δ 8.44 (s, 1H), 8.37-8.55 (b, 1H, CO-NH), 8.22-8.25
(d, 1H), 8.18-8.21 (d, 1H), 7.66-7.71 (dt, 1H), 7.60-7.65 (dt,
1H), 4.33-4.40 (b, 1H), 4.00 (s, 3H, OCH3), 1.20-2.70 (m, 21H).
Analysis results for (C26H33N2O6Br‚1.5H2O) C, H, N are in
Supporting Information.
(S)-N-(1-(Bicyclo[3.3.1]n on -9-yl)-2-p yr r olid in ylm eth yl)-
4-br om o-1-m eth oxy-2-n a p h th a m id e (24). Yield of 21% from
IIc (three steps); mp 69-71 °C (oxalate). 1H NMR (free amine
in CDCl3): δ 8.47 (s, 1H), 8.42-8.44 (b, 1H, CO-NH), 8.23-
8.26 (d, 1H), 8.18-8.21 (d, 1H), 7.66-7.71 (dt, 1H), 7.60-7.65
(dt, 1H), 4.00 (s, 3H, OCH3), 3.68-3.90 (m, 1H), 3.00-3.10 (m,
1H), 1.90-2.10 (m, 2H), 1.40-1.80 (m, 18H), 1.20-1.30 (m,
2H). Analysis results for (C28H35N2O6Br‚2H2O) C, H, N are in
Supporting Information.
(S)-N-(1-(2-Adam an tyl)-2-pyr r olidin ylm eth yl)-4-br om o-
1-m eth oxy-2-n a p h th a m id e (25). Yield of 37% from IIc
1
(three steps); mp 119-121 °C (oxalate). H NMR (free amine
in CDCl3): δ 8.45 (s, 1H), 8.26-8.32 (b, 1H, CO-NH), 8.23-
8.26 (d, 1H), 8.18-8.21 (d, 1H), 7.66-7.71 (dt, 1H), 7.60-7.65
(dt, 1H), 4.00 (s, 3H, OCH3), 3.77-3.90 (m, 1H), 3.15-3.35 (m,
1H), 1.20-2.20 (m, 22H). Analysis results for (C29H35N2O6Br‚
2H2O) C, H, N are in Supporting Information.
Data from dopamine receptor competition experiments were
modeled using nonlinear regression analysis to determine the
concentration of inhibitor that inhibits 50% of the specific
binding of the radioligand (IC50 value). IC50 values were
converted to equilibrium dissociation constants (Ki values)
using the Cheng and Prusoff correction.26 The Kd value used
for [125I]IABN at D2 and D3 dopamine receptors expressed in
Sf9 cells was 0.05 and 0.04 nM, respectively.36 Nonlinear curve-
fitting procedures utilized J andel Scientific Tablecurve soft-
ware. All competitive radioligand binding studies were per-
formed with n g 3, and the Ki values are reported as the mean
with (SEM (standard error of the mean).
(R)-N-(1-Cyclobu tyl-2-p yr r olid in ylm eth yl)-4-br om o-1-
m eth oxy-2-n a p h th a m id e (27). Yield of 48% from IId (three
steps); mp 95-97 °C (oxalate). 1H NMR (free amine in
CDCl3): δ 8.46 (s, 1H), 8.36-8.42 (b, 1H, CO-NH), 8.19-8.26
(m, 2H), 7.62-7.69 (m, 2H), 4.35 (m, 1H), 4.05 (s, 3H), 4.02 (s,
3H, OCH3), 1.5-3.0 (m, 12). Analysis results for (C23H27N2O6-
Br‚1H2O) C, H, N are in Supporting Information.
(R)-N-(1-Cyclop en tyl-2-p yr r olid in ylm eth yl)-4-br om o-
1-m eth oxy-2-n a p h th a m id e (28). Yield of 53% from IId
1
(three steps); mp 81-83 °C (oxalate). H NMR (free amine in
In Vitr o σ Recep tor Bin d in g Stu d ies. Crude synaptoso-
mal (P2) membrane homogenates were prepared from frozen
guinea pig brains without cerebellum.40,41 Brains were allowed
CDCl3): δ 8.45 (s, 1H), 8.30-8.40 (b, 1H, CO-NH), 8.17-8.24
(m, 2H), 7.61-7.67 (m, 2H), 4.35 (m, 1H), 4.01 (s, 3H, OCH3),

Naphthamides as Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1825
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to thaw slowly on ice before homogenization. Crude P2
membranes were also prepared from the livers of male
Sprague-Dawley rats (300-350 g). The livers were minced
before homogenization at 4 °C, using a Potter-Elvehjem tissue
grinder. The crude homogenate was centrifuged for 10 min at
1000 g and the supernant was kept on ice. The pellet was
resuspended in 2 mL/g tissue weight of ice-cold 10 mM Tris-
HCl/0.32 M sucrose, pH 7.4. After centrifuging at 1000 g for
10 min, the supernatants were combined and centrifuged at
31 000 g for 15 min. The pellet was resuspended in 3 mL/g 10
mM Tris-HCl, pH 7.4, and the suspension was allowed to
incubate at 25 °C for 15 min. Following centrifugation at
31 000 g for 15 min, the aliquots were stored at -80 °C until
used. The protein concentration of the suspension was deter-
mined using the method of Bradford protocol.42
For σ1 receptor binding studies guinea pig brain membrane
homogenates (100 µg of protein) were incubated with 3 nM
[3H](+)-pentazocine (31.6 Ci/mmol) in 50 mM Tris-HCl (pH
8.0) at 25 °C for either 120 or 240 min. Test compounds were
dissolved in ethanol and then diluted in buffer for a total
incubation volume of 0.5 mL. Test compounds were added in
concentrations ranging from 0.005 to 1000 nM. Assays were
terminated by the addition of ice-cold 10 mM Tris-HCl (pH
8.0) followed by rapid filtration through Whatman GF/B glass-
fiber filters (presoaked in 0.5% polyethylenimine) using a
Brandel cell harvester (Gaithersburg, MD). Filters were
washed twice with 5 mL of ice cold buffer. Nonspecific binding
was determined in the presence of 10 µM (+)-pentazocine.
Liquid scintillation counting was carried out in EcoLite(+)
(ICN Radiochemicals; Costa Mesa, CA) using a Beckman LS
6000IC spectrometer with a counting efficiency of 50%.
For σ1 receptor binding studies rat liver membrane homo-
genates (35 µg of protein) were incubated with 3 nM [3H]DTG
(38.3 Ci/mmol) in the presence of 100 nM (+)-pentazocine to
block σ1 receptor binding sites. Incubations were carried out
in 50 mM Tris-HCl (pH 8.0) for 120 min at 25 °C in a total
incubation volume of 0.5 mL. Test compounds were added in
concentrations ranging from 0.005 to 1000 nM. Assays were
terminated by the addition of ice-cold 10 mM Tris-HCl (pH
8.0) followed by rapid filtration through Whatman GF/B glass-
fiber filters (presoaked in 0.5% polyethylenimine) using a
Brandel cell harvester (Gaithersburg, MD). Filters were
washed twice with 5 mL of ice-cold buffer. Nonspecific binding
was determined in the presence of 5 µM DTG. Liquid scintil-
lation counting was carried out in EcoLite(+) (ICN Radio-
chemicals, Costa Mesa, CA) using a Beckman LS 6000IC
spectrometer with a counting efficiency of 50%.
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nonlinear regression analysis of binding data. Ki values were
calculated using the method of Cheng and Prusoff 26 and
reported as mean values with (SEM. The Kd value used for
[3H]DTG in rat liver was 17.9 nM and was 4.8 nM for [3H]-
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Ack n ow led gm en t. This research was supported by
PHS Grants DA 09142, DA 09147, and DA 12647 from
the National Institute on Drug Abuse and by the
Scottish Rite Schizophrenia Research Program.
Su p p or tin g In for m a tion Ava ila ble: Table listing results
from elemental analyses of compounds 1-33. This material
is available free of charge via the Internet at http://pubs.ac-
s.org.
D
2 and D3 receptor binding and quantitative structure-activity
studies on substituted 2,3-dimethoxy-N-(1-benzyl-4-piperidinyl)-
benzamides and related compounds. Med. Chem. Res. 1999, 9,
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