2-Aminotetralin-derived substituted benzamides with mixed dopamine D2, D3, and serotonin 5-HT(1A) receptor binding properties: A novel class of potential atypical antipsychotic agents

Article abstract of DOI:10.1016/S0968-0896(98)00167-9

A new chemical class of potential atypical antypsychotic agents, based on the pharmacological concept of mixed dopamine D₂ receptor antagonism and serotonin 5-HT(1A) receptor agonism, was designed by combining the structural features of the 2-(N,N-di-n-propylamino)tetralins (DPATs) and the 2-pyrrolidinylmethyl-derived substituted benzamides in a structural hybrid. Thus, a series of 35 differently substituted 2-aminotetralin-derived substituted benzamides was synthesized and the compounds were evaluated for their ability to compete for [³H]-raclopride binding to cloned human dopamine D(2A) and D₃ receptors, and for [³H]-8-OH-DPAT binding to rat serotonin 5-HT(1A) receptors in vitro. The lead compound of the series, 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (12a), displayed high affinities for the dopamine D(2A) receptor (K(i)=3.2nM), the dopamine D₃ receptor (K(i)=0.58nM) as well as the serotonin 5-HT(1A) receptor (K(i)=0.82nM). The structure-affinity relationships of the series suggest that the 2-aminotetralin moieties of the compounds occupy the same binding sites as the DPATs in all three receptor subtypes. The benzamidoethyl side chain enhances the affinities of the compounds for all three receptor subtypes, presumably by occupying an accessory binding site. For the dopamine D₂ and D₃ receptors, this accessory binding site may be identical to the binding site of the 2-pyrrolidinylmethyl-derived substituted benzamides. Copyright (C) 1998 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00167-9

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 2111±2126
2-Aminotetralin-derived Substituted Benzamides with Mixed
Dopamine D2, D3, and Serotonin 5-HT1A Receptor Binding
Properties: A Novel Class of Potential Atypical Antipsychotic
Agents
Evert J. Homan,a,* Swier Copinga,a,b Lotta Elfstrom,c Trees van der Veen,a
Jan-Pieter Hallema,a Nina Mohell,b Lena Unelius,b Rolf Johansson,b
Hakan V. Wikstroma and Cor J. Grola
aDepartment of Medicinal Chemistry, University Centre for Pharmacy, University of Groningen, Antonius Deusinglaan 1, NL-9713 AV
Groningen, The Netherlands
bCNS Preclinical R&D, Astra Arcus AB, S-151 85 Sodertalje, Sweden
È
È
cOrganic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Box 574, S-574 23 Uppsala, Sweden
Received 7 April 1998; accepted 8 July 1998
AbstractÐA new chemical class of potential atypical antypsychotic agents, based on the pharmacological concept of
mixed dopamine D2 receptor antagonism and serotonin 5-HT1A receptor agonism, was designed by combining the
structural features of the 2-(N,N-di-n-propylamino)tetralins (DPATs) and the 2-pyrrolidinylmethyl-derived substituted
benzamides in a structural hybrid. Thus, a series of 35 di€erently substituted 2-aminotetralin-derived substituted ben-
zamides was synthesized and the compounds were evaluated for their ability to compete for [3H]-raclopride binding to
cloned human dopamine D2A and D3 receptors, and for [3H]-8-OH-DPAT binding to rat serotonin 5-HT1A receptors
in vitro. The lead compound of the series, 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (12a), dis-
played high anities for the dopamine D2A receptor (Ki=3.2 nM), the dopamine D3 receptor (Ki=0.58 nM) as well as
the serotonin 5-HT1A receptor (Ki=0.82 nM). The structure±anity relationships of the series suggest that the 2-ami-
notetralin moieties of the compounds occupy the same binding sites as the DPATs in all three receptor subtypes. The
benzamidoethyl side chain enhances the anities of the compounds for all three receptor subtypes, presumably by
occupying an accessory binding site. For the dopamine D2 and D3 receptors, this accessory binding site may be iden-
tical to the binding site of the 2-pyrrolidinylmethyl-derived substituted benzamides. # 1998 Elsevier Science Ltd. All
rights reserved.
Introduction
been the subject of many investigations during the last
decade. Based on cluster analyses, performed on the
receptor binding pro®les of a number of classical and
supposedly atypical antipsychotic agents, Meltzer and
co-workers hypothesized that compounds which com-
bine 5-HT2 receptor antagonism and dopamine D2
receptor antagonism in an appropriate ratio (5-HT2/D2
pKi ratio51.12) should possess atypical antipsychotic
properties. This hypothesis should thus account for the
superior clinical pro®le of clozapine, the standard aty-
pical antipsychotic agent.1,2 Based on this concept of
mixed 5-HT2/dopamine D2 receptor antagonism, several
In the search for new atypical antipsychotic agents,
which combine a superior clinical ecacy with a low
incidence risk in causing extrapyramidal side-e€ects
(EPS) and tardive dyskinesias (TD), compounds with
mixed dopaminergic and serotonergic properties have
Key words: Dopamine; serotonin; atypical antipsychotics; 2-
aminotetralins; benzamides.
*Corresponding author. Tel.: +31-50-3633303; fax: +31-50-
3636808; e-mail: ejh@farm.rug.nl
0968-0896/98/$ - see front matter # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00167-9

2112
E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
new potential atypical antipsychotic agents have been
developed during recent years, including risperidone,3
seroquel,4 and sertindole.5 Risperidone, which is now
clinically available, has been show to possess improved
ecacy against the negative symptoms of schizophrenia
and a reduced EPS liability.6
semi-rigid 2-aminotetralin (2-amino-1,2,3,4-tetrahydro-
naphthalene) system has been successfully applied as a
template for the development of dopaminergic,22 ser-
otonergic,23 adrenergic,24,25 and melatonergic26 agents
in the past. Particularly, the hydroxylated N,N-di-n-
propyl-substituted 2-aminotetralins (DPATs) have been
shown to possess intriguing structure±activity relation-
ships with regard to dopaminergic and serotonergic
receptors. For example, 5-hydroxy-2-(N,N-di-n-propyl-
amino)tetralin (5-OH-DPAT, 4), 6-hydroxy-2-(N,N-
di-n-propylamino)tetralin (6-OH-DPAT, 5) and 7-
hydroxy-2-(N,N-di-n-propylamino)tetralin (7-OH-DPAT,
6) are highly potent to weak dopamine D2 receptor
agonists, in the potency order of 456>5,27±30 whereas
the 8-hydroxy analogue (8-OH-DPAT, 7) is a potent
serotonin 5-HT1A receptor agonist devoid of dopami-
nergic activity.23 Furthermore, the unsubstituted analo-
gue 2-(N,N-di-n-propylamino)tetralin (DPAT, 8) has
been shown to possess mixed dopaminergic and ser-
otonergic properties.31 Thus, the activity pro®le of the
DPATs can be tuned by the substitution pattern on the
aromatic nucleus. Taken together, we conceived it pos-
sible to develop compounds with the desired receptor
binding pro®le by linking the basic nitrogen of di€er-
ently substituted 2-aminotetralins via a two-carbon
chain to the amide nitrogen of di€erently substituted
benzamide moieties (Fig. 1). Therefore, a series of N-(2-
benzamidoethyl)-substituted 2-(N-n-propylamino)tetra-
lins with various substitution patterns at the aromatic
nuclei of the 2-aminotetralin and benzamide moieties
was synthesized, and the ability of these compounds to
compete for [3H]-raclopride binding to cloned human
dopamine D2A and D3 receptors and [3H]-8-OH-DPAT
binding to rat serotonin 5-HT1A receptors in vitro was
determined.
Selective serotonin 5-HT1A receptor agonists have been
shown to interact with antipsychotic agents in beha-
vioural and neurochemical models. For example, 8-
hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OH-DPAT,
7, Chart 1) has been reported to reverse catalepsy,
induced by haloperidol7±11 or raclopride12 in rats. Fur-
thermore, 8-OH-DPAT has been shown to possess
antipsychotic-like properties in models predictive of
antipsychotic activity13,14 and to enhance some anti-
psychotic-like e€ects of raclopride in rats.12 In addition,
it has been suggested that serotonin 5-HT1A receptor
agonism may be bene®cial in relieving the anxiety that
can trigger psychotic episodes in schizophrenics.15
Taken together, these ®ndings suggest that compounds
which combine dopamine D2 receptor antagonism with
serotonin 5-HT1A receptor agonism may have enhanced
antipsychotic activity and a reduced EPS liability.
Recently, several laboratories have disclosed new com-
pounds with the indicated receptor binding pro®les and
demonstrable atypical antipsychotic-like properties in
preclinical models.15±18
This promising new approach in the search for atypical
antipsychotic agents encouraged us to develop a new
chemical class of compounds with mixed dopamine D2
and serotonin 5-HT1A receptor binding properties. The
benzamide moiety was chosen as a starting point for the
design of this series. Substituted benzamides, in parti-
cular those of the 2-pyrrolidinylmethyl class, are known
for their high anity and selectivity towards dopamine
D2 and D3 receptors. Some of these compounds (e.g.
sulpiride (1), remoxipride (2) and raclopride (3)) possess
atypical antipsychotic properties.19±21 In order to incor-
porate serotonergic activity into the benzamide moiety,
we decided to combine this pharmacophore with the
2-aminotetralin system in one structural hybrid. The
Chemistry
The synthetic pathway employed to obtain the target
compounds is outlined in Scheme 1. The appropriately
substituted 2-(N-n-propylamino)tetralins 9a±e, known
from the literature,32±34 served as starting points for the
Chart 1.

E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
2113
11a±e. Three di€erent methods were employed to
obtain the amides 12a±o, 13a±d, 14a±d, 15a±d and 16a±d.
First, the appropriate acid chloride (either commercially
available or readily obtained from the corresponding
carboxylic acid using standard procedures) was
employed in the presence of sodium hydroxide and the
biphasic medium water/dichloromethane according
to the Schotten±Baumann procedure (Method A).26
Second, the appropriate acid chloride was allowed to
react with the appropriate primary amine in boiling
chloroform, without addition of a base (Method B).35
Third, the appropriate carboxylic acid was converted
into a mixed anhydride using ethyl chloroformate and
was then allowed to react with the appropriate primary
amine in the presence of triethylamine and acetone as
the solvent (Method C).36 Since in the DPAT series the
hydroxy-substituted congeners usually have the highest
anities, compounds 12a, 13a, 14a and 15a were deme-
thylated with boron tribromide in dichloromethane,37
resulting in the corresponding hydroxy analogues 12p,
13e, 14e and 15e, respectively (Scheme 2).
Figure 1. Schematic representation of the structural hybridiza-
tion of 2-pyrrolidinylmethyl-derived substituted benzamides
(A) and 2-(N,N-di-n-propylamino)tetralins (DPATs, B), result-
ing in the concept of 2-aminotetralin-derived benzamides (C).
Pharmacology
synthesis of the target compounds. N-alkylation with
bromoacetonitrile in boiling acetone, employing potas-
sium carbonate as a base and potassium iodide as a
catalyst, gave the cyanomethyl intermediates 10a±e in
good yields, which subsequently were reduced almost
quantitatively with LiAlH4 to the corresponding amines
Compounds 12a±p, 13a±e, 14a±e, 15a±e, and 16a±d
were evaluated for their ability to compete for [3H]-
raclopride binding to cloned human dopamine D2A
receptors (expressed in Ltk cells) and cloned human
dopamine D3 receptors (expressed in CHO cells), and
their ability to compete for [3H]-8-OH-DPAT binding to
Scheme 1. Reagents and conditions: (a) BrCH2CN, K2CO3, KI, acetone, Á; (b) LiAlH4, THF, Á; (c) ArCOCl, 10% NaOH, CH2Cl2;
(d) ArCOCl, CHCl3, Á; (e) ArCOOH, EtOCOCl, Et3N, acetone.

2114
E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
Scheme 2. Reagents: (a) BBr3, CH2Cl2, 50 ꢀC.
rat hippocampal membranes containing serotonin 5-
HT1A receptors in vitro. Haloperidol and clozapine were
evaluated in the same assays for comparison purposes.
The results of these binding studies are shown in Table 1.
group and the carbonyl oxygen atom, resulting in an
out-of-plane conformation of the entire aromatic ring
with respect to the amide functionality. These assump-
tions are supported by X-ray and molecular modeling
studies performed on 2-pyrrolidinylmethyl-derived ben-
zamides with comparable substitution patterns.19±21 It
should be noted, however, that the dopamine D2A/D3
receptor anity ratio is also a€ected by substituents at
other positions of the benzamide moiety. This becomes
obvious when the anities of compounds 12a±c, 12e,
12f, 12i, and 12k for these receptor subtypes are com-
pared. Introduction of an ortho-methoxy group in 12a,
resulting in 12b, decreases the anities for both receptor
subtypes considerably. Introduction of an additional
methoxy group at the 3-position, as in 12c, restores the
high anity for the dopamine D2A receptor (cf. 12a),
but decreases the dopamine D3 receptor anity even
more (cf. 12b). Thus, the preference of compounds 12c,
13b, 14b, and 15b for the dopamine D2A receptor, as
compared to their 2,6-dimethoxy-substituted analogues
12d, 13c, 14c, and 15c, seems not only to be accounted
for by the ability of 12c, 13b, 14b, and 15b to form an
intramolecular hydrogen bond, as opposed to 12d, 13c,
14c, and 15c, but also by the presence of the 3-methoxy
group, which enhances the dopamine D2A receptor a-
nity and at the same time decreases the dopamine D3
receptor anity. The anities of compounds 12e, 12f,
12i, and 12k reveal that substitution of the benzamide 5-
position, in combination with an ortho-methoxy group
(cf. 12g and h), also restores some of the anity for the
dopamine D2A receptor (cf. 12b). These observations
are in line with SAR and QSAR studies performed on
2-pyrrolidinylmethyl-derived benzamides, which have
shown that a 2,3-dimethoxy substitution pattern,38±40
and the presence of a lipophilic and/or bulky substituent
at the 5-position19,41,42 are favourable for high dopa-
mine D2 receptor anity. Therefore, the benzamide
moieties of the 2-aminotetralin-derived benzamides
presented here may occupy the same binding site as
the 2-pyrrolidinylmethyl-derived benzamides.
Results and discussion
By linking di€erently substituted benzamide moieties, as
present in the 2-pyrrolidinylmethyl-derived class of sub-
stituted benzamides, with their amide nitrogen atom via
a 2-carbon chain to the basic nitrogen atoms of di€er-
ently substituted 2-N-n-propylaminotetralins, we have
attempted to combine the pharmacological properties of
these two distinct classes of compounds into a new che-
mical class of compounds (i.e. the 2-aminotetralin-
derived benzamides). The results of the binding assays
in Table 1 show that most compounds display moderate
to high anities for dopamine D2A and D3, and ser-
otonin 5-HT1A receptors.
When considering the e€ects of di€erently substituted
benzamide moieties, several consistent trends can be
observed in the binding data: compounds with a 2,3-
dimethoxy substitution pattern on the benzamide moi-
ety (12c, 14b, 15b, and 16b) always have a higher anity
for the dopamine D2A receptor than for the dopamine
D3 receptor, whereas for compounds with a 2,6-dime-
thoxy substitution pattern (12d, 14c, 15c, and 16c) the
opposite is the case (i.e. they prefer the dopamine D3
receptor to the dopamine D2 receptor). These remark-
able consistencies in anities towards the two dopamine
receptor subtypes should probably be explained by dif-
ferences in conformational behaviour of the two types
of substituted benzamides. Compounds with one meth-
oxy substituent positioned ortho towards the benzamide
carbonyl group presumably adopt a conformation in
which the ortho-methoxy group is oriented in a coplanar
fashion with respect to the plane of the aromatic ring
and amide group, while forming a hydrogen bond
between its oxygen atom and the amide hydrogen atom
(Fig. 2). Benzamides with a 2,6-dimethoxy substitution
pattern cannot adopt such a coplanar system due to
steric hindrance between the second ortho-methoxy
Whereas 2-pyrrolidinylmethyl-derived substituted ben-
zamides generally need several lipophilic substituents
on the aromatic nucleus for high anity, this is not

E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
2115
Table 1. Receptor binding data of compounds 12a±p, 13a±e, 14a±e, 15a±e, and 16a±d, haloperidol, and clozapine
Ki (nM)a
Compd
R
Ar
D2A
D3
5-HT1A
12a
12b
12c
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OCH3
5-OH
Phb
2-OCH3-Ph
2,3-di-OCH3-Ph
2,6-di-OCH3-Ph
5-Br-2-OCH3-Ph
5-I-2-OCH3-Ph
5-Br-2-OH-Ph
2-OH-5-I-Ph
2-OCH3-5-SO2NH2-Ph
5-Br-2,6-di-OCH3-Ph
4-NH2-5-Cl-2-OCH3-Ph
2-Thienyl
3.2‹0.2
22.9‹8.4
6.7‹2.7
47.9‹16.0
9.4‹1.0
6.9‹2.3
79.8‹2.0
266‹110
14.7‹2.7
42.8‹3.2
2.9‹0.5
3.6‹0.2
5.4‹1.8
21.9‹0.3
18.5‹2.9
1.4‹0.2
70.8‹7.6
10.1‹1.0
1070‹70
112‹11
0.58‹0.05
19.7‹5.6
24.3‹1.4
2.6‹0.1c
17.4‹0.5
16.3‹0.7
NDd
0.82‹0.11
15.2‹6.9
12.7‹4.5
27.3‹1.6
38.5‹23.0
75‹45
12d
12e
12f
12g
12h
12i
10.4‹1.6
21.9‹0.4
34.4‹6.4
53.9‹20.6
40.5‹1.5
1.1‹0.1
ND
20.3‹1.1
ND
12j
12k
12l
2.5‹0.2
0.69‹0.05
ND
12m
12n
12o
12p
13a
13b
13c
3-Thienyl
1-Napthyl
4.6‹0.5
ND
ND
13.0‹2.8
20.2‹3.8
1.5‹0.4
2-Naphthyl
Ph
Ph
0.28‹0.03
ND
ND
6-OCH3
6-OCH3
6-OCH3
6-OCH3
6-OH
16.8‹4.3
72.8‹12.4
93.0‹23.7
61.1‹8.3
17.4‹4.7
4.2‹1.1
2,3-di-OCH3-Ph
2,6-di-OCH3-Ph
2-Thienyl
ND
ND
13d
13e
Ph
Ph
13.4‹2.4
60.7‹0.9
3.7‹0.1
366‹51
ND
14a
14b
14c
7-OCH3
7-OCH3
7-OCH3
7-OCH3
7-OH
14.3‹0.7c
6.8‹0.4
56.2‹0.2
32.7‹6.6
0.50‹0.03
4.5‹0.7
14.6‹0.4
15.0‹2.0
9.8‹1.8
6.8‹2.3c
0.46‹0.01
7.4‹0.1
2.6‹0.1
ND
2,3-di-OCH3-Ph
2,6-di-OCH3-Ph
2-Thienyl
12.7‹1.2
32.8‹0.6
12.2‹0.4
3.0‹1.2
14d
14e
110‹4
Ph
Ph
3.7‹0.1
54.9‹1.8
1.0‹0.1
89.5‹1.3
60.3‹4.1
55.2‹2.2
10.0‹0.8
0.63‹0.1
59.8‹9.3
106‹18
15a
15b
15c
8-OCH3
8-OCH3
8-OCH3
8-OCH3
8-OH
<0.3
0.76‹0.11
1.0‹0.1
2,3-di-OCH3-Ph
2,6-di-OCH3-Ph
2-Thienyl
15d
15e
0.73‹0.19
<0.3
Ph
Ph
16a
16b
16c
H
0.56‹0.05
3.5‹0.3
3.7‹0.4
H
2,3-di-OCH3-Ph
2,6-di-OCH3-Ph
2-Thienyl
H
16d
Haloperidol
Clozapine
H
1.8‹0.3
2,213‹585
304‹184
0.67‹0.11
59.8‹7.8
2.7‹0.6
83.3‹9.9
aMean values‹SEM of two to four independent experiments.
bPh: phenyl.
cTwo binding sites signi®cant.
dND: not determined.
necessary for the 2-aminotetralin-derived benzamides:
comparison of the anities of 12a with those of 12b±k
shows that attachment of substituents on the benzamide
nucleus generally leads to somewhat lower anities.
Furthermore, the benzene ring of the benzamide moi-
ety of 12a can be replaced by aromatic isosteres of
comparable size, such as 2-thiophene (12l) and 3-thio-
phene (12m) without seriously a€ecting the anities for
the receptors. A similar isosteric replacement in 15a
does not a€ect the receptor binding (cf. 15d) either, but
in 13a, 14a, and 16a it results in lower anities (cf.
13d, 14d and 16d, respectively). Replacement by larger

2116
E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
the large 2-benzamidoethyl side chain is tolerated well
by the three receptor subtypes is constistent with the
requirements for the nitrogen substituents of the
DPATs, where only one substituent larger than n-propyl
is allowed.43±49 Taken together, the ®ndings suggest that
the 2-benzamidoethyl side chain may occupy an acces-
sory binding site in all three receptor subtypes, thereby
enhancing the anities for the receptors. For the dopa-
minergic receptors, this accessory binding site may
prove to be identical to the binding site of the 2-
pyrrolidinylmethyl-derived substituted benzamides, as
noted earlier.
Figure 2. Conformational di€erences between 2-methoxy (A)
and 2,6-dimethoxy-substituted (B) benzamides: intramolecular
hydrogen bond formation in A results in a coplanar benzene
ring and amide, whereas in B the presence of a second ortho-
methoxy group causes steric hindrance with the carbonyl oxy-
gen atom and hence an out-of-plane twisted benzene ring.
Since both the DPATs and the 2-pyrrolidinylmethyl-
derived substituted benzamides display high stereo-
selectivity in their interactions with the receptors, it
may be anticipated that this will also be the case for
the 2-aminotetralin-derived benzamides. Therefore,
compounds 12a and d were selected for enantiopure
synthesis and assessment of the in vitro receptor binding
pro®les and the intrinsic ecacies at dopamine D2, D3
and serotonin 5-HT1A receptors of their enantiomers.
aromatic systems, such as 1-naphthalene (12n) or 2-
naphthalene (12o) results in somewhat lower anities
when compared to their benzene analogue (12a).
Apparently, these groups are too bulky to be accom-
modated optimally by the receptors.
When the e€ects of the di€erently substituted amino-
tetralin moieties are examined, several conclusions can
be drawn. First, when comparing the dopaminergic
anities of 5-, 6- and 7-methoxy-substituted congeners
with identically substituted benzamide moieties (e.g.
12a, 13a, and 14a), the general order of potency (except
for the 2,3-dimethoxy-substituted benzamides) is 5-
OCH3>7-OCH3>6-OCH3. Furthermore, the hydroxy-
substituted congeners (12p, 13e, and 14e) all have higher
anitities than their methoxy-substituted analogues. In
addition, all congeners with an 8-methoxy substitutent
have a very high anity for the serotonin 5-HT1A
receptor. Similar to 8-OH-DPAT,43 replacement of the
8-methoxy group by a hydroxy group (cf. 15a and e)
does not a€ect the anity for the serotonin 5-HT1A
receptor. Nevertheless, the binding data of compounds
16a±d show that substituents on the aminotetralin
nucleus are not a prerequisite for high anities. Taken
together, these structure±anity relationships are con-
sistent with those of the DPATs23,27±29,31 and suggest
that the 2-aminotetralin part of the molecules occupy
the same binding sites as the DPATs.
Conclusions
A series of compounds with mixed dopamine D2, D3,
and serotonin 5-HT1A receptor binding pro®les was
designed by combining the structural and pharmacolo-
gical features of two distinct classes of compounds, the
2-pyrrolidinylmethyl-derived substituted benzamides
and the DPATs, into a new basic skeleton. Several
compounds display high anities for both dopamine D2
and D3, and serotonin 5-HT1A receptors. Provided that
they have the desired intrinsic ecacies at the indicated
receptor subtypes, these compounds may be interesting
candidates for further evaluation of the dopamine D2/
serotonin 5-HT1A hypothesis of atypical antipsychotic
activity.
Experimental
Chemistry
Finally, the binding data suggest that attachment of a
2-benzamidoethyl side chain to the basic nitrogen atom
of di€erently substituted 2-(N-n-propylamino)tetralins
enhances the anities for the dopamine D2 and D3, as
well as for the serotonin 5-HT1A receptor, when com-
pared to their DPAT analogues. For example, whereas
5-OH-DPAT (4) and 7-OH-DPAT (6) have virtually no
serotonergic activity, their benzamide analogues 12p
and 14e have high anities for the serotonin 5-HT1A
receptor. On the other hand, compound 15e has mod-
erate and high anity for the dopamine D2 and D3
receptor, respectively, whereas 8-OH-DPAT (7) is
devoid of dopaminergic activity. The observation that
General remarks. Unless otherwise indicated, all mate-
rials were purchased from commercial suppliers and used
without further puri®cation. All basic amine products
were converted to their corresponding hydrochloride or
oxalate salts by adding an equimolar amount of a 1 M
etheral HCl solution or an ethanolic solution of oxalic
acid to a solution of the free base in ether. All chemical
data, except for TLC analyses and electron impact mass
spectra, were obtained on the salt forms, unless other-
wise stated. TLC analyses were carried out on alumi-
nium plates (E. Merck) precoated with silica gel 60 F254

E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
2117
(0.2 mm), and spots were visualised with UV light and
I2. Gravity column chromatography was performed
using silica gel (E. Merck 60). Melting points were deter-
mined in open glass capillaries on an electrothermal
digital melting-point apparatus and are uncorrected. IR
spectra (KBr pellets) were recorded on an ATI-Mattson
Genesis Series FT-IR spectrophotometer, and only the
important absorptions are indicated. Broad peaks (b)
have been indicated as such. 1H NMR spectra were
recorded at 200 MHz on a Varian Gemini-200 spectro-
meter or at 300 MHz on a Varian VXR-300 spectro-
5-Methoxy-2-(N-cyanomethyl-N-n-propylamino)tetralin
hydrochloride (10a). Yield 85%; mp 183±186 ꢀC; IR:
1
1
cm 2924, 2832, 2739, 2347 (b), 1590; H NMR (base,
200 MHz, CDCl3): d 0.97 (t, J=7.3 Hz, 3H), 1.46±1.75
(m, 3H), 2.14±2.22 (m, 1H), 2.52±3.07 (m, 7H), 3.68 (s,
2H), 3.84 (s, 3H), 6.72 (dd, J=8.4 Hz, 8.4 Hz, 2H), 7.14
(t, J=7.8 Hz, 1H); 13C NMR (base, 50 MHz, CDCl3): d
11.6, 20.9, 26.5, 33.2, 38.6, 52.1, 55.2, 57.7, 107.2, 116.9,
121.5, 124.8, 126.4, 136.4, 157.1; MS (EI, 70 eV) m/z
(rel. intensity) 104 (47), 123 (60), 134 (64), 161 (100), 229
(33), 258 (58, M+).
1
meter. H NMR chemical shifts are denoted in d units
(ppm) relative to the solvent and converted to the TMS
scale, using 7.26 for CDCl3 and 3.30 for CD3OD. The
following abbreviations are used to indicate spin multi-
plicities: s (singlet), bs (broad singlet), d (doublet), dd
(doublet of doublets), t (triplet), m (multiplet). 13C
NMR spectra were recorded at 50 MHz on a Varian
Gemini-200 spectrometer or at 75 MHz on a Varian
VXR-300 spectrometer. 13C NMR chemical shifts are
denoted in d units (ppm) relative to the solvent and
converted to the TMS scale, using 76.91 for CDCl3 and
49.50 for CD3OD. Chemical ionization (CI) mass spec-
tra were recorded on a Finnegan 3300 quadrupole mass
spectrometer. Ammonia was used as the reactant gas
and samples were introduced into the ion source by
means of the direct insertion probe. Alternatively, che-
mical ionization mass spectra were recorded on a
NERMAG R 3010 triple quadrupole mass spectrometer
equipped with a home-built atmospheric pressure ioni-
zation source and ionspray interface. Electron impact
(EI) mass spectra were recorded on a Unicam 610/
Automass 150 mass spectrometer in conjunction with a
gas chromatograph. Elemental analyses (C, H, and N)
for target compounds were performed at the Micro
Analytical Department, University of Groningen, and
unless otherwise indicated, the obtained results were
within 0.4% of the theoretical values.
6-Methoxy-2-(N-cyanomethyl-N-n-propylamino)tetralin
hydrochloride (10b). Using the general procedure, this
compound was prepared from 9b HCl.34 Yield 30%; mp
.
138±140 ꢀC; IR: cm 2936, 2839, 2344 (b), 1611; 1H
1
NMR (base, 200 MHz, CDCl3): d 0.93, (t, J=7.3 Hz,
3H), 1.46±1.78 (m, 3H), 2.07±2.17 (m, 1H), 2.65±3.03
(m, 7H), 3.66 (s, 2H), 3.77 (s, 3H), 6.63 (d, J=2.7 Hz,
1H), 6.70 (dd, J=8.3 Hz, 2.7 Hz, 1H), 7.00 (d,
J=8.3 Hz, 1H); 13C NMR (base, 50 MHz, CDCl3): d
11.3, 20.7, 26.5, 28.8, 32.1, 38.4, 51.9, 55.0, 58.1, 112.0,
113.0, 116.8, 126.8, 130.1, 136.8, 157.7; MS (EI, 70 eV):
m/z (rel. intensity) 91 (41), 134 (98), 161 (100), 199 (15),
229 (52), 258 (61, M+).
7-Methoxy-2-(N-cyanomethyl-N-n-propylamino)tetralin
hydrochloride (10c). This compound was synthesized
33
.
from 9c HCl using the general procedure. Yield 73%;
mp 144±146 ꢀC; IR: cm 2922, 2832, 2737, 2365 (b),
1
1616; 1H NMR (base, 200 MHz, CDCl3): d 0.96 (t,
J=7.3 Hz, 3H), 1.44±1.71 (m, 3H), 2.09±2.17 (m, 1H),
2.66±3.00 (m, 7H), 3.64 (s, 2H), 3.77 (s, 3H), 6.64±6.74
(m, 2H), 7.00 (dd, J=8.6 Hz, 1H); 13C NMR (base,
50 MHz, CDCl3): d 11.4, 20.7, 26.8, 27.8, 33.1, 38.4,
51.8, 55.0, 58.0, 112.3, 113.7, 116.9, 127.8, 129.3, 136.1,
156.7; MS (EI, 70 eV): m/z (rel. intensity) 91 (24), 134
(100), 161 (85), 218 (20), 229 (20), 258 (54, M+).
8-Methoxy-2-(N-cyanomethyl-N-n-propylamino)tetralin
hydrochloride (10d). Using the general procedure, this
General procedure for the preparation of compounds
10a±e
compound was prepared from 9d HCl.33 Yield 62%; mp
.
1
The method adopted for the synthesis of 5-methoxy-
2-(N-cyanomethyl-N-n-propylamino)tetralin hydro-
163±164 ꢀC; IR: cm 2943, 2839, 2305 (b), 1584; 1H
NMR (base, 200 MHz, CDCl3): d 0.99 (t, J=7.3 Hz, 3H),
1.48±1.75 (m, 3H), 2.13±2.20 (m, 1H), 2.53 (dd,
J=16.0 Hz, 9.6 Hz, 1H), 2.74 (dd, J=7.2 Hz, 7.2 Hz, 2H),
2.84±3.13 (m, 4H), 3.68 (s, 2H), 3.85 (s, 3H), 6.72 (dd,
J=8.4 Hz, 8.4 Hz, 2H), 7.14 (t, J=7.8 Hz, 1H); 13C NMR
(base, 50 MHz, CDCl3): d 11.4, 20.8, 26.1, 26.8, 29.0, 38.4,
52.0, 55.0, 57.9, 106.8, 116.9, 120.6, 123.7, 126.2, 137.2,
157.3; MS (EI, 70 eV): m/z (rel. intensity) 91 (16), 104 (27)
123 (20), 134 (28), 161 (100), 229 (24), 258 (47, M+).
chloride (10a) is described: bromoacetonitrile (1.17 g,
33
.
9.8 mmol) was added to a suspension of 9a HCl
(1.00 g, 3.9 mmol), K2CO3 (1.35 g, 9.8 mmol) and KI
(0.16 g, 0.1 mmol) in acetone (50 mL). The reaction
mixture was re¯uxed for 18 h under a nitrogen atmo-
sphere. After cooling, the solids were removed by ®ltra-
tion and the ®ltrate was concentrated under reduced
pressure, which yielded the crude nitrile as a dark brown
oil. Puri®cation by column chromatography (eluent:
CH2Cl2) gave 0.86 g (3.3 mmol) of the pure base of 10a
as a colourless oil, which was converted to the hydro-
chloride salt.
2-(N-Cyanomethyl-N-n-propylamino)tetralin hydro-
chloride (10e). Using the general procedure, this com-
32
.
pound was prepared from 9e HCl. Yield 69%; mp

2118
E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
158±160 ꢀC; IR: cm 3138, 3022, 2933, 2364 (b) 1578;
1H NMR (base, 200 MHz, CDCl3): d 0.97 (t, J=7.3 Hz,
3H), 1.44±1.83 (m, 3H), 2.12±2.20 (m, 1H), 2.73 (dd,
J=7.5 Hz, 7.5 Hz, 2H), 2.82±3.09 (m, 5H), 3.69 (s, 2H),
7.14 (s, 4H); 13C NMR (base, 50 MHz, CDCl3): d 11.6,
20.9, 26.8, 28.8, 33.1, 38.9, 52.1, 58.1, 116.9, 125.8,
126.0, 128.6, 129.4, 135.0, 135.9; MS (EI, 70 eV): m/z
(rel. intensity) 104 (22), 131 (100), 199 (18), 228 (16, M+).
IR: cm 2937, 2836, 2670 (b), 2527 (b), 1719, 1612; H
1
1
1
NMR (base, 200 MHz, CDCl3): d 0.89 (t, J=7.3 Hz,
3H), 1.40±1.65 (m, 3H), 1.93±2.02 (m, 3H), 2.43±2.59
(m, 4H), 2.67±2.96 (m, 7H), 3.75 (s, 3H), 6.61±6.69 (m,
2H), 6.95±6.99 (m, 1H); 13C NMR (base, 50 MHz,
CDCl3): d 11.6, 22.1, 25.7, 28.9, 32.2, 40.3, 52.3, 52.8,
55.0, 56.3, 111.9, 113.7, 128.4, 129.3, 137.6, 157.4; MS
(CI with AcOH): m/z 220 (7), 234 (5), 263 (100, M+1).
8-Methoxy-2-[N-(2-aminoethyl)-N-n-propylamino]tetralin
dihydrochloride (11d). Using the general procedure, this
compound was prepared from 10d. Yield 97%; mp 155±
General procedure for the preparation of compounds
11a±e
157 ꢀC; IR: cm 3396 (b), 2939, 2837, 2637 (b), 2520
1
The method adopted for the synthesis of 5-methoxy-2-
[N-(2-aminoethyl)-N-n-propylamino]tetralin dihydro-
chloride (11a) is described: a solution of the free base of
10a (10.00 g, 38.7 mmol) in dry THF (75 mL) was added
dropwise to a stirred, ice-cooled suspension of LiAlH4
(3 g) in dry THF (75 mL). When addition was complete,
the reaction mixture was re¯uxed overnight under a
nitrogen atmosphere. After cooling, excess LiAlH4 was
quenched by subsequent addition of H2O (3 mL), 4 N
aqueous NaOH solution (3 mL) and H2O (9 mL). After
drying over Na2SO4, the suspension was ®ltrated and
the ®ltrate was concentrated under reduced pressure,
yielding 10.09 g (38.5 mmol) of the pure base of 11a as a
clear yellow oil, which was converted to the dihydro-
chloride salt.
1
(b), 1587; H NMR (base, 200 MHz, CDCl3): d 0.91 (t,
J=7.3 Hz, 3H), 1.39±1.70 (m, 3H), 1.80 (bs, 2H), 1.91±
2.03 (m, 1H), 2.36±3.01 (m, 11H), 3.82 (s, 3H), 6.68 (dd,
J=8.8 Hz, 8.8 Hz, 2H), 7.08 (t, J=7.9 Hz, 1H); 13C
NMR (base, 50 MHz, CDCl3): d 11.8, 22.4, 25.6, 30.3,
40.6, 52.6, 53.1, 55.1, 56.6, 106.7, 120.8, 125.3, 125.9,
137.8, 157.5; MS (CI with AcOH): m/z (rel. intensity)
220 (23), 234 (32), 263 (100, M+1).
2-[N-(2-Aminoethyl)-N-n-propylamino]tetralin dihydro-
chloride (11e). Using the general procedure, this com-
pound was prepared from 10e. Yield 96%; mp 138±
141 ꢀC; IR: cm 1 3402 (b), 2965, 2643 (b), 2522 (b), 2043
1
(b), 1607; H NMR (base, 200 MHz, CDCl3): d 0.91 (t,
J=7.3 Hz, 3H), 1.39±1.68 (m, 5H), 1.96±2.06 (m, 1H),
2.46±3.01 (m, 11H), 7.10 (s, 4H); 13C NMR (base,
50 MHz, CDCl3): d 11.8, 22.3, 25.8, 29.9, 32.1, 40.7,
52.6, 53.1, 56.5, 125.6, 128.6, 129.4, 135.0, 135.5; MS
(EI, 70 eV): m/z (rel. intensity) 72 (23), 131 (100), 202
(79), 232 (2, M+).
5-Methoxy-2-[N-(2-aminoethyl)-N-n-propylamino]tetralin
dihydrochloride (11a). Yield 99%; mp 112±114 ꢀC (lit.46
mp 110±112 ꢀC); IR: cm 3406 (b), 2965, 2836, 2631
1
1
(b), 2520 (b), 2063 (b), 1588; H NMR (base, 200 MHz,
CDCl3): d 0.88 (t, J=7.3 Hz, 3H), 1.39±1.55 (m, 5H),
1.97±2.04 (m, 1H), 2.41±3.02 (m, 11H), 3.75 (s, 3H), 6.62
(dd, J=15.6 Hz, 7.8 Hz, 2H), 7.04 (t, J=7.9 Hz, 1H);
13C NMR (base, 50 MHz, CDCl3): d 11.6, 22.1, 23.7,
25.2, 32.0, 40.5, 52.3, 52.9, 54.8, 55.9, 106.6, 121.5,
125.0, 126.0, 137.9, 157.1; MS (EI, 70 eV): m/z (rel.
intensity) 72 (10), 161 (50), 232 (100), 262 (1, M+).
General procedures for the preparation of compounds
12a±o, 13a±d, 14a±d, 15a±d and 16a±d
Method A. The method adopted for the synthesis of 5-
methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]te-
tralin hydrochloride (12a) is described: benzoyl chloride
(4.70 g, 33.4 mmol), dissolved in CH2Cl2 (25 mL), was
added dropwise to a ®rmly stirred mixture of CH2Cl2
(225 mL), 10% aqueous NaOH solution (40 mL) and
11a (4.00 g, 11.9 mmol). After stirring overnight at room
temperature, the reaction mixture was poured into H2O
(50 mL) and the phases were separated. The aqueous
layer was extracted with CH2Cl2 (2Â100 mL), the
organic layers were combined and subsequently washed
with saturated aqueous NaHCO3 solution (3Â100 mL),
H2O (100 mL) and brine (100 mL). The organic layer
was dried (Na2SO4), ®ltrated and concentrated under
reduced pressure, which gave the crude amide as a
brown oil. Puri®cation by column chromatography
(eluent: MeOH/CH2Cl2, 1/15 (v/v)) yielded 1.68 g
(4.6 mmol) of the pure base of 12a as a colourless oil,
which was converted to the hydrochloride salt.
6-Methoxy-2-[N-(2-aminoethyl)-N-n-propylamino]tetralin
dihydrochloride (11b). Using the general procedure, this
compound was prepared from 10b. Yield 98%; mp 113±
115 ꢀC; IR: cm 3414 (b), 2965, 2837, 2639 (b), 2517,
1
2055 (b), 1610; 1H NMR (base, 200 MHz, CDCl3): d
0.88 (t, J=7.3 Hz, 3H), 1.40±1.69 (m, 3H), 1.95±2.15 (m,
1H), 2.43±2.95 (m, 11H), 3.75 (s, 3H), 6.61 (d, J=2.2 Hz,
1H), 6.66 (dd, J=8.3 Hz, 2.7 Hz, 1H), 6.99 (d, J=8.3 Hz,
1H); 13C NMR (base, 50 MHz, CDCl3): d 11.6, 22.1,
25.5, 30.0, 31.0, 40.4, 52.4, 52.9, 55.0, 56.5, 111.8, 113.0,
128.5, 130.1, 137.4, 157.5; MS (CI with AcOH): m/z (rel.
intensity) 220 (7), 234 (14), 263 (100, M+1).
7-Methoxy-2-[N-(2-aminoethyl)-N-n-propylamino]tetralin
oxalate (11c). Using the general procedure, this com-
pound was prepared from 10c. Yield 97%; mp 168±170 ꢀC;

E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
2119
Method B. The method adopted for the synthesis of 5-
methoxy-2-{N-[2-(2,3-dimethoxy)benzamidoethyl]-N-n-
propylamino}tetralin hydrochloride (12c) is described: a
solution of 2,3-dimethoxybenzoyl chloride (0.72 g,
3.6 mmol) in CDCl3 (10 mL) was added dropwise to a
boiling solution of the free base of 11a (0.375 g,
1.4 mmol) in CDCl3 (15 mL). When addition was com-
plete, the reaction mixture was allowed to cool to room
temperature and stirring was continued overnight. The
reaction mixture was transferred to a separatory funnel
and subsequently washed with saturated NaHCO3
solution (3Â20 mL), H2O (20 mL) and brine (20 mL).
After drying (Na2SO4) and ®ltration, the organic layer
was concentrated under reduced pressure, which gave
the crude amide as a brown oil. Puri®cation by column
chromatography (eluent: MeOH/CH2Cl2, 1/20 (v/v))
yielded 0.28 g (0.7 mmol, 46%) of the pure base of 12c
as a colourless oil, which was converted to the hydro-
chloride salt.
134.6, 137.3, 157.1, 167.1; MS (CI with NH3): m/z (rel.
intensity) 78 (6), 161 (2), 232 (8), 367 (100, M+1); Anal.
.
(C23H30N2O2 HCl ˆH2O) C, H, N.
.
5-Methoxy-2-{N-[2-(2-methoxy)benzamidoethyl]-N-n-
propylamino}tetralin hydrochloride (12b). Method B.
Yield 92%; mp 88±92 ꢀC; IR: cm 1 3335 (b), 2939, 2837,
2593 (b), 2499 (b), 1640, 1597, 1523; 1H NMR (base,
200 MHz, CDCl3): d 0.92 (t, J=7.3 Hz, 3H), 1.43±1.71
(m, 3H), 2.02±2.12 (m, 1H), 2.46±3.10 (m, 9H), 3.53±
3.61 (m, 2H), 3.81 (s, 3H), 3.98 (s, 3H), 6.68 (dd,
J=7.3 Hz, 7.3 Hz, 2H), 6.97±7.14 (m, 3H), 7.41±7.50 (m,
1H), 8.26 (dd, J=7.9 Hz, 1.9 Hz, 1H), 8.43 (bs, 1H); 13
C
NMR (base, 50 MHz, CDCl3): d 11.8, 22.3, 23.9, 25.5,
32.1, 38.4, 48.7, 52.3, 55.2, 55.7, 56.1, 106.9, 111.2,
121.1, 121.5, 121.8, 125.1, 126.2, 132.2, 132.5, 137.8,
157.2, 157.6, 165.1; MS (CI with NH3): m/z (rel. inten-
sity) 72 (21), 135 (41), 161 (62), 178 (14), 232 (100), 397
.
(38, M+1); Anal. (C24H32N2O3 HCl ˆH2O) C, H, N.
.
Method C. The method adopted for the synthesis of
5-methoxy-2-{N-[2-(4-amino-5-chloro-2-methoxy)benz-
5-Methoxy-2-{N-[2-(2,3-dimethoxy)benzamidoethyl]-N-
n-propylamino}tetralin hydrochloride (12c). Method B.
Yield 46%; mp 113±116 ꢀC; IR: cm 3420 (b), 2981,
1
amidoethyl]-N-n-propylamino}tetralin
hydrochloride
(12k) is described: ethyl chloroformate (81 mg, 0.7 mmol)
was added to a stirred solution of 4-amino-5-chloro-2-
methoxybenzoic acid (150 mg, 0.7 mmol) and triethyl-
amine (75 mg, 0.7 mmol) in acetone (5 mL) at 0 ꢀC. Stir-
ring was continued for 1 h at 0 ꢀC, upon which a white
solid precipitated. Then 11a (250 mg, 0.7 mmol) was
added, immediately followed by a second amount of
triethylamine (100 mg, 1.0 mmol). Stirring was again
continued for 1 h at 0 ꢀC, and then the precipitate was
removed from the reaction mixture by ®ltration. The
®ltrate was concentrated under reduced pressure, the
resulting residue was dissolved in CH2Cl2 (50 mL) and
the organic solution was subsequently washed with
saturated aqueous NaHCO3 solution (3Â25 mL), H2O
(25 mL) and brine (25 mL). After drying (Na2SO4) and
®ltration, the organic solution was concentrated in
vacuo, which yielded the crude amide as a light brown
oil. After puri®cation by column chromatography
(eluent: MeOH/CH2Cl2, 1/15 (v/v)), 150 mg (0.3 mmol,
43%) of the pure base of 12k was obtained as a colour-
less oil, which was converted to the hydrochloride salt.
2838, 2667 (b), 2519 (b), 1660, 1611, 1538; 1H NMR
(base, 200 MHz, CDCl3): d 0.89 (t, J=7.3 Hz, 3H),
1.41±1.69 (m, 3H), 2.02±2.12 (m, 1H), 2.43±2.61 (m,
3H), 2.74±3.06 (m, 6H), 3.51±3.59 (m, 2H), 3.80 (s, 3H),
3.91 (s, 6H), 6.67 (dd, J=8.5 Hz, 8.5 Hz, 2H), 7.01±7.19
(m, 3H), 7.71 (dd, J=7.8 Hz, 1.7 Hz, 1H), 8.40 (bs, 1H);
13C NMR (base, 50 MHz, CDCl3): d 11.6, 22.1, 23.6,
25.3, 31.7, 38.2, 48.7, 52.1, 55.0, 55.8, 56.1, 61.1, 106.7,
114.9, 121.5, 122.7, 124.1, 125.0, 126.0, 126.9, 137.7,
147.5, 152.5, 157.1, 165.0; MS (CI with NH3): m/z (rel.
intensity) 182 (6), 232 (6) 427 (100, M+1); Anal.
.
.
(C25H34N2O4 HCl H2O) C, H, N.
5-Methoxy-2-{N-[2-(2,6-dimethoxy)benzamidoethyl]-N-
n-propylamino}tetralin hydrochloride (12d). Method A.
Yield 59%; mp 113±116 ꢀC; IR: cm 3400 (b), 2939,
1
2837, 2630 (b), 2519 (b), 1655, 1595, 1524; 1H NMR
(base, 200 MHz, CDCl3): d 0.86 (t, J=7.3 Hz, 3H),
1.41±1.61 (m, 3H), 1.99±2.05 (m, 1H), 2.43±2.55 (m,
3H), 2.73±2.88 (m, 4H), 2.94±3.05 (m, 2H), 3.49±3.56
(m, 2H), 3.80 (s, 9H), 6.43 (bs, 1H), 6.56 (d, J=8.6 Hz,
2H), 6.66 (dd, J=7.1 Hz, 7.1 Hz, 2H), 7.08 (t, J=7.8 Hz,
1H), 7.28 (t, J=7.4 Hz, 1H); 13C NMR (base, 50 MHz,
CDCl3): d 11.6, 21.8, 23.6, 25.2, 31.8, 37.6, 48.7, 51.9,
55.0, 55.6, 55.8, 103.7, 106.8, 116.1, 121.4, 124.9, 126.1,
130.3, 137.7, 157.1, 157.3, 165.6; MS (CI with NH3): m/z
(rel. intensity) 232 (6), 427 (100, M+1); Anal. (C25H34
5-Methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]-
tetralin hydrochloride (12a). Method A. Yield 39%; mp
91±93 ꢀC; IR: cm 1 3267, 2938, 2836, 2611 (b), 2517 (b),
1654, 1588, 1540; 1H NMR (base, 200 MHz, CDCl3): d
0.92 (t, J=7.3 Hz, 3H), 1.42±1.71 (m, 3H), 1.99±2.08 (m,
1H), 2.45±2.63 (m, 3H), 2.75±2.86 (m, 4H), 2.93±3.07
(m, 2H), 3.45±3.55 (m, 2H), 3.80 (s, 3H), 6.67 (dd,
J=7.4 Hz, 7.4 Hz, 2H), 7.06±7.13 (m, 2H), 7.40±7.52 (m,
3H), 7.78±7.83 (m, 2H); 13C NMR (base, 50 MHz,
CDCl3): d 11.6, 21.8, 23.5, 25.3, 31.9, 37.6, 48.3, 51.9,
55.0, 55.6, 106.8, 121.4, 124.9, 126.1, 126.7, 128.4, 131.1,
.
N2O4 HCl ‰H2O) C, H, N.
.
5-Methoxy-2-{N-[2-(5-bromo-2-methoxy)benzamidoethyl]-
N-n-propylamino}tetralin hydrochloride (12e). Method
A. Yield 49%; mp 108±110 ꢀC; IR: cm 1 3328 (b), 2938,
2837, 2596 (b), 2478 (b), 1649, 1590, 1522; 1H NMR

2120
E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
(base, 300 MHz, CDCl3): d 0.91 (t, J=7.3 Hz, 3H),
1.56±1.70 (m, 3H), 2.11±2.13 (m, 1H), 2.47±2.66 (m,
3H), 2.82±3.13 (m, 6H), 3.55±3.62 (m, 2H), 3.79 (s, 3H),
3.96 (s, 3H), 6.66 (dd, J=7.9 Hz, 3.8 Hz, 2H), 6.87 (d,
J=8.8 Hz, 1H), 7.08 (t, J=7.9 Hz, 1H), 7.52 (dd,
J=8.8 Hz, 2.9 Hz, 1H), 8.30 (d, J=2.6 Hz, 1H), 8.45
(bs, 1H); 13C NMR (base, 75 MHz, CDCl3): d 11.6,
23.5, 38.0, 49.0, 55.1, 56.0, 107.0, 113.1, 113.6, 121.3,
123.3, 124.7, 126.3, 129.2, 134.7, 135.0, 156.6, 157.1,
163.8; MS (CI with NH3): m/z (rel. intensity) 72 (19),
161 (27), 232 (58), 475 (100, M[Br ˆ 79]+1), 477
1H), 7.68 (dd, J=8.5 Hz, 2.2 Hz, 1H), 8.15 (d,
J=2.0 Hz); 13C NMR (300 MHz, CD3OD): d 11.3, 19.5,
23.6, 24.6, 30.6, 37.3, 52.2, 54.4, 55.8, 61.9, 109.0, 119.5,
120.6, 122.3, 124.5, 128.2, 134.5, 138.8, 143.7, 158.5,
159.8, 170.4; MS (CI with NH3): m/z (rel. intensity) 180
(16), 223 (12), 383 (100), 509 (7, M+1); Anal.
.
(C23H29N2O3I HCl) C, H, N.
5-Methoxy-2-{N-[2-(2-methoxy-5-sulfamoyl)benzamido-
ethyl]-N-n-propylamino}-tetralin hydrochloride (12i).
Method C. Yield 32%; mp 177±178 ꢀC; IR: cm 3317,
1
.
.
(100, M[Br ˆ 81]+1); Anal. (C24H31N2O3Br HCl H2O)
3188 (b), 3072 (b), 2941, 2841, 2485 (b), 2363, 1632,
1591, 1528; 1H NMR (300 MHz, CD3OD): d 1.07 (t,
J=7.6 Hz, 3H), 1.87±1.96 (m, 3H), 2.34±2.42 (m, 1H),
2.62±2.70 (m, 1H), 3.07±3.45 (m, 6H), 3.63±3.69 (m,
1H), 3.80 (s, 3H), 3.83±3.89 (m, 3H), 4.05 (s, 3H), 6.68±
6.77 (m, 2H), 7.11 (t, J=7.3 Hz, 1H), 7.31 (d, J=8.8 Hz,
1H), 8.04 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.50 (d,
J=2.0 Hz, 1H); 13C NMR (75 MHz, CD3OD): d 10.6,
18.8, 22.9, 23.8, 30.0, 37.3, 52.0, 53.9, 55.1, 56.7, 61.1,
108.3, 112.9, 121.3, 121.6, 123.9, 127.5, 130.1, 132.1,
133.9, 136.9, 157.8, 161.0, 167.8; MS (EI, 70 eV): m/z 86
C, H, N.
5-Methoxy-2-{N-[2-(5-iodo-2-methoxy)benzamidoethyl]-
N-n-propylamino}tetralin hydrochloride (12f). Method
A. Yield 46%; mp 110±112 ꢀC; IR: cm 1 3337 (b), 2937,
2837, 2598 (b), 2502 (b), 1644, 1586, 1523; 1H NMR
(base, 200 MHz, CDCl3): d 0.90 (t, J=7.3 Hz, 3H),
1.45±1.68 (m, 3H), 2.03±2.08 (m, 1H), 2.47±2.59 (m,
3H), 2.72±2.83 (m, 4H), 2.97±3.05 (m, 2H), 3.51±3.57
(m, 2H), 3.80 (s, 3H), 3.94 (s, 3H), 6.66 (dd, J=7.3 Hz,
7.3 Hz, 2H), 6.75 (d, J=8.8 Hz, 1H), 7.08 (t, J=7.8 Hz,
1H), 7.70 (dd, J=8.8 Hz, 2.6 Hz, 1H), 8.32 (bs, 1H),
8.49 (d, J=2.6 Hz, 1H); 13C NMR (base, 50 MHz,
CDCl3): d 11.6, 21.9, 23.7, 25.3, 31.9, 38.2, 48.7, 52.2,
55.1, 55.8, 56.2, 106.9, 107.7, 113.5, 121.4, 123.8, 124.9,
126.1, 128.5, 140.6, 140.8, 157.1, 157.2, 163.5; MS (CI
with NH3): m/z (rel. intensity) 161 (4), 232 (10), 523
(68), 161 (100), 204 (49), 232 (71), 355 (7), 377 (9), 432
+
.
(4), 461 (7), 475 (13, M ); Anal. (C24H34N3O5S HCl) C,
H, N.
5-Methoxy-2-{N-[2-(5-bromo-2,6-dimethoxy)benzamido-
ethyl]-N-n-propylamino}-tetralin hydrochloride (12j).
Method B. Yield 36%; mp 193±195 ꢀC; IR: cm 3183,
1
1
.
(100, M+1); Anal. (C24H31N2O3I HCl H2O) C, H, N.
.
2940, 2835, 2575 (b), 1661, 1587, 1541; H NMR (base,
200 MHz, CDCl3): d 0.85 (t, J=7.3 Hz, 3H), 1.40±1.64
(m, 3H), 1.96±2.05 (m, 1H), 2.24±3.04 (m, 9H), 3.47±
3.57 (m, 2H), 3.79 (s, 3H), 3.80 (s, 3H), 3.88 (s, 3H), 6.45
(bs, 1H), 6.58±6.70 (m, 3H), 7.10 (t, J=7.8 Hz, 1H), 7.49
(d, J=8.8 Hz, 1H); 13C NMR (base, 50 MHz, CDCl3): d
11.5, 21.6, 23.5, 25.1, 31.7, 37.8, 48.5, 52.0, 55.0, 55.8,
62.2, 106.8, 108.0, 108.2, 121.4, 123.0, 124.9, 126.1,
133.7, 137.5, 154.6, 156.5, 157.1, 164.4; MS (CI with
AcOH): m/z (rel. intensity) 506 (94, M[Br ˆ 79]+1), 508
5-Methoxy-2-{N-[2-(5-bromo-2-hydroxy)benzamidoethyl]-
N-n-propylamino}tetralin hydrochloride (12g). Method
B. Yield 15%; mp 106±109 ꢀC; IR: cm 1 3225 (b), 2937,
2837, 2608 (b), 2508 (b), 1638, 1589, 1542; 1H NMR
(200 MHz, CD3OD): d 1.02 (t, J=7.3 Hz, 3H), 1.74±
1.95 (m, 3H), 2.31 (bs, 1H), 2.55±2.68 (m, 1H), 3.01±
3.42 (m, 9H), 3.49±3.62 (m, 2H), 3.75 (s, 3H), 6.71 (m,
2H), 6.85 (d, J=8.8 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H),
7.47 (dd, J=8.8 Hz, 2.6 Hz, 1H), 7.94 (d, J=2.2 Hz,
1H); 13C NMR (base, 50 MHz, CDCl3): d 11.3, 17.7,
22.6, 23.8, 28.6, 35.7, 51.5, 54.5, 55.3, 60.6, 108.0, 110.9,
115.3, 119.9, 121.1, 124.5, 127.3, 130.0, 132.4, 137.2,
157.1, 160.5, 169.8; MS (CI with NH3): m/z (rel. inten-
sity) 72 (24), 91 (10), 161 (76), 232 (100), 461 (17,
M[Br ˆ 79]+1), 463 (17, M[Br ˆ 81]+1); Anal. (C23H29
.
.
(100, M[Br ˆ 81]+1); Anal. (C25H33N2O4Br HCl ˆH2O)
C, H, N.
5-Methoxy-2-{N-[2-(4-amino-5-chloro-2-methoxy)benz-
amidoethyl]-N-n-propylamino}tetralin hydrochloride (12k).
Method C. Yield 43%; mp 135±137 ꢀC; IR: cm 3394,
1
1
3319, 3204, 2940, 2835, 2434 (b), 1637, 1589, 1534; H
.
.
N2O3Br HCl ‰H2O) C, H, N.
NMR (base, 200 MHz, CDCl3): d 0.88 (t, J=7.3 Hz,
3H), 1.40±1.68 (m, 3H), 2.02±2.11 (m, 1H), 2.42±2.58
(m, 3H), 2.66±2.81 (m, 4H), 2.94±3.05 (m, 2H), 3.46±
3.52 (m, 2H), 3.79 (s, 3H), 3.87 (s, 3H), 4.48 (bs, 2H),
6.32 (s, 1H), 6.66 (dd, J=6.7 Hz, 6.7 Hz, 2H), 7.07 (t,
J=7.8 Hz, 1H), 8.11 (s, 1H), 8.24 (bs, 1H); 13C NMR
(base, 50 MHz, CDCl3): d 11.5, 21.8, 23.6, 25.1, 31.7,
38.0, 48.6, 52.1, 55.0, 55.7, 55.9, 97.6, 106.8, 111.2,
112.4, 121.4, 124.9, 126.1, 132.9, 137.5, 146.5, 157.1,
157.5, 164.4; MS (CI with NH3): m/z (rel. intensity) 72
5-Methoxy-2-{N-[2-(2-hydroxy-5-iodo)benzamidoethyl]-
N-n-propylamino}tetralin hydrochloride (12h). Method
B. Yield 68%; mp 102±105 ꢀC; IR: cm 3414 (b), 3216
1
(b), 2939, 2836, 2610 (b), 2510 (b), 1637, 1588, 1542; 1H
NMR (300 MHz, CD3OD): d 1.06 (t, J=7.1 Hz, 3H),
1.83±1.95 (m, 3H), 2.33±2.38 (m, 1H), 2.62±2.70 (m,
1H), 3.07±3.43 (m, 7H), 3.61±3.64 (m, 1H), 3.80 (s, 3H),
3.81±3.83 (m, 2H), 6.69±6.77 (m, 3H), 7.11 (t, J=8.1 Hz,

E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
2121
(17), 161 (18), 201 (14), 220 (21), 232 (15), 446 (100,
.
M+1); Anal. (C24H31N3O3 HCl) C, H, N.
(m, 3H), 2.04±2.09 (m, 1H), 2.58 (dd, J=7.3 Hz, 7.3 Hz,
3H), 2.79±2.83 (m, 4H), 2.95±3.05 (m, 2H), 3.51±3.61
(m, 2H), 3.78 (s, 3H), 6.65 (t, J=7.5 Hz, 2H), 7.07 (t,
J=7.8 Hz, 1H), 7.32 (bs, 1H), 7.49±7.59 (m, 2H), 7.82±
7.94 (m, 4H), 8.34 (s, 1H); 13C NMR (base, 50 MHz,
CDCl3): d 11.6, 21.6, 23.5, 25.1, 31.8, 37.7, 48.4, 52.1,
55.0, 55.9, 106.9, 121.4, 123.4, 124.8, 126.2, 126.5, 127.3,
127.4, 127.6, 128.3, 128.9, 131.8, 132.6, 134.5, 137.1,
157.1, 167.2; MS (CI with AcOH): m/z 417 (M+1);
5-Methoxy-2-[N-(2-thiophen-2-carboxamidoethyl)-N-n-
propylamino]tetralin hydrochloride (12l). Method A.
Yield 62%; mp 102±105 ꢀC; IR: cm 3238 (b), 2938,
1
2836, 2608 (b), 2497 (b), 1640, 1588, 1543; 1H NMR
(300 MHz, CD3OD): d 1.00 (m, 3H), 1.84±2.18 (m, 3H),
2.52±2.65 (m, 2H), 2.96±3.04 (m, 2H), 3.08±3.47 (m,
4H), 3.61±3.70 (m, 2H), 3.79 (s, 3H), 3.89±3.99 (m, 2H),
6.62 (dd, J=33.5 Hz, 7.5 Hz, 1H), 6.75 (dd, J=8.1 Hz,
2.20 Hz, 1H), 7.04±7.18 (m, 2H), 7.66±7.70 (m, 1H), 8.18
(dd, J=7.3 Hz, 3.7 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d 11.0, 17.4, 22.4, 28.4, 30.0, 35.8, 51.5, 54.4,
55.0, 60.6, 107.7, 121.0, 123.1, 127.0, 128.1, 129.4, 130.5,
132.6, 138.3, 156.9, 162.7; MS (CI with NH3): m/z (rel.
intensity) 161 (3), 232 (6), 373 (100, M+1); Anal.
.
Anal. (C27H32N2O2 HCl H2O) C, H, N.
.
6-Methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]-
tetralin hydrochloride (13a). Method A. Yield 77%; mp
76±78 ꢀC; IR: cm 1 3245 (b), 2938, 2835, 2479 (b), 1654,
1
1610, 1578, 1534; H NMR (base, 200 MHz, CDCl3): d
0.91 (t, J=7.3 Hz, 3H), 1.45±1.63 (m, 3H), 1.95±2.18 (m,
1H), 2.54 (dd, J=7.3 Hz, 7.3 Hz, 2H), 2.70±3.09 (m,
7H), 3.47±3.58 (m, 2H), 3.75 (s, 3H), 6.61±6.71 (m, 2H),
6.95±7.15 (m, 2H), 7.38±7.49 (m, 3H), 7.79±7.83 (m,
2H); 13C NMR (base, 50 MHz, CDCl3): d 11.6, 21.7,
25.5, 29.7, 31.0, 37.7, 48.4, 52.0, 55.0, 56.3, 111.9, 113.0,
126.7, 130.1, 131.2, 134.6, 137.1, 157.6, 167.1; MS (EI,
70 eV): m/z (rel. intensity) 77 (28), 105 (36), 161 (100),
.
(C21H28N2O2S HCl ˆH2O) C, H, N.
.
5-Methoxy-2-[N-(2-thiophen-3-carboxamidoethyl)-N-n-
propylamino]tetralin hydrochloride (12m). Method B.
Yield 20%; mp 93±95 ꢀC; IR: cm 1 3232 (b), 3061, 2938,
2835, 2479 (b), 1653, 1588, 1543; 1H NMR (base,
200 MHz, CDCl3): d 0.92 (t, J=7.3 Hz, 3H), 1.46±1.66
(m, 3H), 2.00±2.05 (m, 1H), 2.55 (dd, J=7.4 Hz, 7.4 Hz,
3H), 2.74±2.83 (m, 4H), 2.94±3.06 (m, 2H), 3.44±3.52
(m, 2H), 3.81 (s, 3H), 6.68 (dd, J=6.7 Hz, 6.7 Hz, 2H),
6.94 (bs, 1H), 7.10 (t, J=7.9 Hz, 1H), 7.32±7.41 (m, 2H),
7.85 (s, 1H); 13C NMR (base, 50 MHz, CDCl3): d 11.6,
21.6, 23.4, 25.2, 31.9, 37.3, 48.3, 51.9, 55.0, 55.7, 106.9,
121.4, 124.8, 125.8, 126.2, 126.3, 127.8, 137.2, 157.1,
162.8; MS (CI with AcOH): m/z 373 (M+1); Anal.
.
.
232 (83), 366 (2, M+); Anal. (C23H30N2O2 HCl ˆH2O)
C, H, N.
6-Methoxy-2-{N-[2-(2,3-dimethoxy)benzamidoethyl]-N-
n-propylamino}tetralin hydrochloride (13b). Method A.
Yield 37%; mp 83±85 ꢀC; IR: cm 1 3353 (b), 2937, 2835,
2465 (b), 1647, 1611, 1578, 1505; 1H NMR (base,
200 MHz, CDCl3): d 0.88 (t, J=7.3 Hz, 3H), 1.40±1.72
(m, 3H), 1.98±2.16 (m, 1H), 2.49±2.60 (m, 2H), 2.68±
3.04 (m, 7H), 3.50±3.58 (m, 2H), 3.74 (s, 3H), 3.89 (s,
3H), 3.90 (s, 3H), 6.59±6.69 (m, 2H), 6.94±7.17 (m, 3H),
7.70 (dd, J=7.0 Hz, 1.7 Hz, 1H), 8.38 (bs, 1H); 13C
NMR (base, 50 MHz, CDCl3): d 11.6, 22.1, 25.6, 29.9,
30.8, 38.3, 48.8, 52.2, 55.0, 55.8, 56.7, 61.1, 111.8, 113.0,
114.9, 122.6, 124.1, 126.9, 128.2, 130.1, 137.3, 147.5,
152.5, 157.5, 165.0; MS (EI, 70 eV): m/z (rel. intensity)
.
.
(C21H28N2O2S HCl ˆH2O) C, H, N.
5-Methoxy-2-[N-(2-naphthalen-1-carboxamidoethyl)-N-n-
propylamino]tetralin hydrochloride (12n). Method B.
Yield 45%; mp 152±153 ꢀC; IR: cm 3232 (b), 2939,
1
2835, 2512 (b), 1655, 1588, 1522; 1H NMR (base,
200 MHz, CDCl3): d 0.88 (t, J=7.3 Hz, 3H), 1.43±1.62
(m, 3H), 1.98±2.06 (m, 1H), 2.54 (dd, J=7.3 Hz, 7.3 Hz,
3H), 2.75±2.79 (m, 4H), 2.89±3.08 (m, 2H), 3.50±3.61
(m, 2H), 3.81 (s, 3H), 6.65 (dd, J=7.8 Hz, 4.2 Hz, 2H),
6.91 (bs, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.42±7.64 (m, 4H),
91 (12), 122 (9), 161 (100), 202 (7), 232 (98), 383 (2), 426
+
.
(2, M ); Anal. (C25H34N2O4 HCl ˆH2O) C, H, N.
.
6-Methoxy-2-{N-[2-(2,6-dimethoxy)benzamidoethyl]-N-
n-propylamino}tetralin hydrochloride (13c). Method A.
Yield 76%; mp 83±85 ꢀC; IR: cm 1 3240 (b), 2939, 2838,
2606 (b), 2499 (b), 1655, 1596, 1503; 1H NMR
(300 MHz, CD3OD): d 1.10 (t, J=7.3 Hz, 3H), 1.88±2.00
(m, 3H), 2.35±2.37 (m, 1H), 2.98±3.27 (m, 5H), 3.36±3.44
(m, 2H), 3.60±3.65 (m 1H), 3.75 (s, 3H), 3.77 (s, 3H),
3.80 (s, 3H), 3.88±3.91 (m, 1H), 6.69±6.76 (m, 4H), 7.08
(d, J=8.3Hz, 1H), 7.35±7.39 (m, 1H); 13C NMR (75 MHz,
CD3OD): d 11.3, 19.7, 24.5, 29.5, 37.9, 53.7, 54.3, 55.7,
56.4, 61.9, 105.1, 114.1, 115.1, 125.3, 131.2, 132.8, 137.1,
158.6, 159.9, 172.1; MS (EI, 70 eV): m/z (rel. intensity)
7.89 (dd, J=7.8 Hz, 7.8 Hz, 2H), 8.39±8.44 (m, 1H); 13
C
NMR (base, 50 MHz, CDCl3): d 11.7, 21.9, 23.6, 25.2,
31.9, 38.0, 48.5, 52.1, 55.0, 55.8, 106.9, 121.5, 124.7,
124.8, 124.9, 125.5, 126.2, 126.8, 128.2, 130.1, 130.3,
133.6, 134.7, 137.5, 157.1, 169.4; MS (CI with AcOH):
.
m/z 417 (M+1); Anal. (C27H32N2O2 HCl ‰H2O) C,
.
H, N.
2-[N-(2-Naphthalen-2-carboxamidoethyl)-N-n-propyl-
amino]-5-methoxytetralin hydrochloride (12o). Method
B. Yield 35%; mp 117±119 ꢀC; IR: cm 3246, 2938,
1
2835, 2479 (b), 1653, 1588, 1534; 1H NMR (base,
200 MHz, CDCl3): 0.92 (t, J=7.3 Hz, 3H), 1.44±1.69
91 (18), 161 (100), 232 (98), 267 (10), 383 (5), 426 (3,
+
. .
M ); Anal. (C25H34N2O4 HCl ‰H2O) C, H, N.

2122
E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
6-Methoxy-2-[N-(2-thiophen-2-carboxamidoethyl)-N-n-
propylamino]tetralin hydrochloride (13d). Method B.
Yield 36%; mp 88±90 ꢀC; IR: cm 1 3244 (b), 3059, 2937,
2837, 2609 (b), 2486 (b), 1640, 1611, 1543; 1H NMR
(base, 200 MHz, CDCl3): d 0.91 (t, J=7.3 Hz, 3H),
1.42±1.74 (m, 3H), 1.96±2.03 (m, 1H), 2.54 (dd,
J=8.2 Hz, 6.5 Hz, 2H), 2.63±3.09 (m, 7H), 3.39±3.51 (m,
2H), 3.76 (s, 3H), 6.60±6.71 (m, 2H), 6.95±7.10 (m, 3H),
7.43±7.53 (m, 2H); 13C NMR (base, 50 MHz, CDCl3): d
11.6, 21.6, 25.4, 29.7, 30.9, 37.4, 48.2, 52.0, 55.0, 56.2,
111.9, 113.0, 127.5, 127.7, 127.8, 129.4, 130.1, 137.1,
139.2, 157.6, 161.7; MS (EI, 70 eV): m/z (rel. intensity)
37.6, 48.9, 52.0, 55.0, 55.6, 56.3, 103.7, 111.9, 113.8,
116.0, 128.2, 129.3, 130.3, 137.2, 157.3, 157.4, 165.7; MS
(CI with NH3): m/z (rel. intensity) 161 (14), 182 (27),
232 (26), 267 (14), 427 (100, M+1); Anal. (C25H34N2O4
3
.
.
HCl
4
H2O) C, H, N.
7-Methoxy-2-[N-(2-thiophen-2-carboxamidoethyl)-N-n-
propylamino]tetralin hydrochloride (14d). Method A.
Yield 27%; mp 80±83 ꢀC; IR: cm 1 3238 (b), 2937, 2837,
2606 (b), 2499 (b), 1638, 1611, 1543; 1H NMR (base,
200 MHz, CDCl3): d 0.94 (t, J=7.3 Hz, 3H), 1.43±1.75
(m, 3H), 1.96±2.08 (m, 1H), 2.54 (dd, J=8.1 Hz, 6.4 Hz,
2H), 2.69±2.86 (m, 6H), 2.94±3.05 (m, 1H), 3.42±3.52
(m, 2H), 3.77 (s, 3H), 6.62 (d, J=2.6 Hz, 1H), 6.70 (dd,
J=8.1 Hz, 2.6 Hz, 1H), 6.89 (bs, 1H), 7.00 (d,
J=8.1 Hz), 7.08±7.12 (m, 1H), 7.45±7.52 (m, 2H); 13C
NMR (base, 50 MHz, CDCl3): d 11.8, 22.1, 26.0, 28.9,
32.4, 37.7, 48.4, 52.0, 55.2, 56.1, 112.1, 113.9, 127.6,
127.9, 128.3, 129.5, 137.2, 157.6, 161.8; MS (CI with
72 (24), 111 (27), 161 (100), 202 (14), 232 (63), 372 (3,
+
.
.
M ); Anal. (C21H28N2O2S HCl ˆH2O) C, H, N.
7-Methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]-
tetralin hydrochloride (14a). Method A. Yield 45%; mp
70±72 ꢀC; IR: cm 3252 (b), 2937, 2836, 2590 (b), 2486
1
1
(b), 1655, 1611, 1578, 1533; H NMR (base, 200 MHz,
.
NH3): m/z 373 (M+1); Anal. (C21H28N2O2S HCl
CDCl3): d 0.93 (t, J=7.5 Hz, 3H), 1.44±1.76 (m, 3H),
1.97±2.07 (m, 1H), 2.57 (dd, J=8.1 Hz, 6.4 Hz, 2H),
2.77±2.83 (m, 6H), 3.00±3.11 (m, 1H), 3.46±3.58 (m,
2H), 3.77 (s, 3H), 6.61 (d, J=2.6 Hz, 1H), 6.70 (dd,
J=8.4 Hz, 2.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 7.04 (bs,
1H), 7.41±7.52 (m, 3H), 7.79±7.84 (m, 2H); 13C NMR
(base, 50 MHz, CDCl3): d 11.8, 22.0, 26.0, 28.9, 32.3,
37.8, 48.6, 52.2, 55.2, 56.3, 112.2, 113.9, 126.8, 128.3,
128.5, 129.5, 131.3, 134.8, 137.3, 157.6, 167.2; MS (CI
.
‰H2O) C, H, N.
8-Methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]-
tetralin hydrochloride (15a). Method A. Yield 48%; mp
107±109 ꢀC; IR: cm 3276 (b), 2981, 2840, 2480 (b),
1
1
1659, 1596, 1542; H NMR (base, 200 MHz, CDCl3): d
0.92 (t, J=7.3 Hz, 3H), 1.43±1.73 (m, 3H), 1.95±2.02 (m,
1H), 2.42±2.62 (m, 3H), 2.73±3.08 (m, 6H), 3.40±3.62
(m, 2H), 3.81 (s, 3H), 6.70 (dd, J=10.1 Hz, 7.9 Hz, 2H),
7.07±7.14 (m, 2H), 7.41±7.56 (m, 3H), 7.82±7.88 (m,
2H); 13C NMR (base, 50 MHz, CDCl3): d 11.6, 22.0,
25.2, 25.7, 29.9, 37.6, 48.2, 52.0, 55.0, 55.9, 106.7, 120.7,
124.7, 126.0, 126.8, 128.4, 131.1, 134.7, 137.5, 157.4,
167.1; MS (CI with AcOH): m/z 367 (M+1); Anal.
.
with NH3): m/z 367 (M+1); Anal. (C23H30N2O2 HCl
.
‰H2O) C, H, N.
7-Methoxy-2-{N-[2-(2,3-dimethoxy)benzamidoethyl]-N-
n-propylamino}tetralin hydrochloride (14b). Method A.
Yield 37%; mp 88±90 ꢀC; IR: cm 1 3345 (b), 2938, 2835,
2461 (b), 1649, 1587, 1516; 1H NMR (200 MHz,
CD3OD): d 1.07 (t, J=7.3 Hz, 3H), 1.85±2.03 (m, 3H),
2.27±2.47 (m, 1H), 2.56±2.77 (m, 1H), 3.03±3.70 (m,
8H), 3.80 (s, 3H), 3.85±3.88 (m, 2H), 3.90 (s, 3H), 3.92
(s, 3H), 6.68±6.79 (m, 2H), 7.09±7.26 (m, 3H), 7.37±7.45
(m, 1H); 13C NMR (50 MHz, CD3OD): d 11.0, 19.1,
23.2, 24.0, 30.5, 37.7, 52.8, 54.3, 55.3, 56.2, 61.3, 61.6,
108.7, 117.2, 122.0, 122.2, 124.4, 125.1, 127.9, 134.5,
158.3; MS (CI with NH3): m/z (rel. intensity) 232 (6),
.
(C23H30N2O2 HCl 1‰H2O) C, H, N.
.
8-Methoxy-2-{N-[2-(2,3-dimethoxy)benzamidoethyl]-N-
n-propylamino}tetralin hydrochloride (15b). Method A.
Yield 66%; mp 88±92 ꢀC; IR: cm 1 3345 (b), 2936, 2837,
2585 (b), 2461 (b), 1647, 1578, 1514; 1H NMR (base,
200 MHz, CDCl3): d 0.89 (t, J=7.3 Hz, 3H), 1.44±1.67
(m, 3H), 1.97±2.06 (m, 1H), 2.52±2.60 (m, 3H), 2.77±
3.01 (m, 6H), 3.41±3.58 (m, 2H), 3.80 (s, 3H), 3.91 (s,
3H), 3.93 (s, 3H), 6.68 (dd, J=9.8 Hz, 8.1 Hz, 2H), 7.02±
7.19 (m, 3H), 7.73 (dd, J=7.9 Hz, 2.9 Hz, 1H), 8.18 (bs,
1H); 13C NMR (base, 50 MHz, CDCl3): d 11.8, 22.4,
25.5, 25.7, 30.2, 38.5, 48.9, 52.4, 55.1, 56.0, 56.6, 61.3,
106.7, 115.0, 120.7, 122.8, 124.1, 125.1, 126.0, 126.9,
129.2, 137.7, 152.6, 157.7, 165.0; MS (CI with NH3): m/z
(rel. intensity) 161 (47), 182 (97), 220 (24), 232 (50), 267
.
392 (4), 427 (100, M+1); Anal. (C25H34N2O4 HCl
.
‰H2O) C, H, N.
7-Methoxy-2-{N-[2-(2,6-dimethoxy)benzamidoethyl]-N-
n-propylamino}tetralin hydrochloride (14c). Method A.
Yield 41%; mp 114±116 ꢀC; IR: cm 3252 (b), 2939,
1
2837, 2490 (b), 1657, 1595, 1505; 1H NMR (base,
200 MHz, CDCl3): d 0.85 (t, J=7.3 Hz, 3H), 1.41±1.65
(m, 3H), 1.93±2.00 (m, 1H), 2.51 (dd, J=7.4 Hz, 7.4 Hz,
2H), 2.73±3.01 (m, 7H), 3.44±3.58 (m, 2H), 3.75 (s, 3H),
3.78 (s, 6H), 6.43 (bs, 1H), 6.54±6.69 (m, 4H), 6.97 (d,
J=8.3 Hz, 1H), 7.26 (t, J=8.4 Hz, 1H); 13C NMR
(base, 50 MHz, CDCl3): d 11.5, 21.7, 25.6, 28.7, 31.9,
(12), 385 (8), 427 (100, M+1); Anal. (C25H34N2O4
3
.
.
HCl
4
H2O) C, H, N.
8-Methoxy-2-{N-[2-(2,6-dimethoxy)benzamidoethyl]-N-
n-propylamino}tetralin hydrochloride (15c). Method A.
Yield 41%; mp 121±123 ꢀC; IR: cm 3391 (b), 2938,
1

E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
2123
2838, 2605 (b), 2512 (b), 1654, 1596, 1524; 1H NMR
(base, 200 MHz, CDCl3): d 0.85 (t, J=7.3 Hz, 3H),
1.40±1.69 (m, 3H), 1.89±1.96 (m, 1H), 2.33±2.60 (m,
3H), 2.73±2.98 (m, 6H), 3.47±3.56 (m, 2H), 3.78 (s, 9H);
6.46 (bs, 1H), 6.55 (d, J=8.3 Hz, 2H), 6.66 (dd,
J=8.6 Hz, 8.6 Hz, 2H), 7.07 (t, J=7.8 Hz, 1H), 7.26 (t,
J=8.6 Hz, 1H); 13C NMR (base, 50 MHz, CDCl3): d
11.6, 21.9, 25.3, 30.0, 37.7, 48.8, 51.8, 54.9, 55.6, 56.1,
103.7, 106.6, 116.0, 120.7, 124.9, 125.9, 130.2, 137.5,
157.3, 165.7; MS (CI with NH3): m/z (rel. intensity) 60
(31), 139 (17), 161 (30), 182 (100), 220 (23), 267 (15), 427
2-{N-[2-(2,6-Dimethoxy)benzamidoethyl]-N-n-propyl-
amino}tetralin hydrochloride (16c). Method A. Yield
75%; mp 107±110 ꢀC; IR: cm 3241 (b), 2938, 2837,
1
2473 (b), 1656, 1596, 1522; 1H NMR (300 MHz,
CD3OD): d 1.13 (t, J=7.3 Hz, 3H), 1.92±2.04 (m, 3H),
2.38±2.42 (m, 1H), 2.98±3.09 (m, 2H), 3.16±3.35 (m, H),
3.48±3.57 (m, 1H), 3.73±3.79 (m, 2H), 3.83 (s, 6H), 3.88±
3.97 (m, 1H), 6.75 (d, J=8.6 Hz, 2H), 7.16±7.24 (m,
4H), 7.41 (t, J=8.4 Hz, 1H); 13C NMR (75 MHz,
CD3OD): d 11.4, 19.9, 24.8, 29.3, 30.6, 38.2, 53.8, 54.4,
56.4, 61.6, 105.1, 115.3, 127.4, 127.7, 129.6, 130.3, 132.7,
133.8, 136.1, 158.6, 171.8; MS (CI with NH3): m/z (rel.
intensity) 202 (14), 397 (100, M+1); Anal. (C24H32
.
(19, M+1); Anal. (C25H34N2O4 HCl ‰H2O) C, H. N.
.
.
.
N2O3 HCl ‰H2O) C, H, N.
8-Methoxy-2-[N-(2-thiophen-2-carboxamidoethyl)-N-n-
propylamino]tetralin oxalate (15d). Method A. Yield
66%; mp 135±137 ꢀC; IR: cm 3257 (b), 2968, 2833,
2-[N-(2-Thiophen-2-carboxamidoethyl)-N-n-propylamino]-
tetralin hydrochloride (16d). Method A. Yield 62%; mp
93±94 ꢀC; IR: cm 3232 (b), 3059, 2937, 2609 (b), 2480
1
2787 (b), 2662 (b), 1718, 1642, 1588, 1541; 1H NMR
(200 MHz, CD3OD): d 1.03 (t, J=7.3 Hz, 3H), 1.79±
1.90 (m, 3H), 2.14±2.26 (m, 1H), 2.67±2.94 (m, 3H),
3.19±3.34 (m, 4H), 3.45±3.56 (m, 2H), 3.71±3.93 (m,
6H), 6.68±6.75 (m, 2H), 7.07±7.17 (m, 2H), 7.69±7.78
(m, 2H); 13C NMR (50 MHz, CD3OD): d 9.6, 17.8, 22.7,
23.1, 27.7, 36.0, 50.8, 53.1, 54.1, 60.5, 106.9, 120.1,
120.5, 126.8, 127.6, 129.3, 131.2, 135.7, 137.3, 157.1,
164.7; MS (CI with AcOH): m/z 373 (M+1); Anal.
1
(b), 1639, 1543; 1H NMR (base, 200 MHz, CDCl3): d
0.94 (t, J=7.3 Hz, 3H), 1.44±1.76 (m, 3H), 1.98±2.07 (m,
1H), 2.56 (dd, J=8.1 Hz, 6.5 Hz, 2H), 2.71±3.12 (m,
7H), 3.39±3.57 (m, 2H), 7.04±7.14 (m, 6H), 7.45 (dd,
J=5.0 Hz, 1.1 Hz, 1H), 7.55 (dd, J=3.7 Hz, 1.0 Hz, 1H);
13C NMR (base, 50 MHz, CDCl3): d 11.7, 21.7, 25.5,
29.5, 31.8, 37.6, 48.3, 52.0, 56.1, 125.6, 125.7, 127.6,
127.8, 128.5, 129.3, 129.5, 135.8, 136.1, 139.2, 161.7; MS
(CI with AcOH): m/z 343 (M+1); Anal. (C20H26N2
.
(C21H28N2O2S C2H2O4) C, H, N.
.
.
OS HCl ˆH2O) C, H, N.
2-[N-(2-Benzamidoethyl)-N-n-propylamino)tetralin hydro-
chloride (16a). Method A. Yield 62%; mp 83±86 ꢀC;
1
IR: cm 3436 (b), 3250 (b), 3060, 2936, 2610 (b), 2512
1
General procedure for the preparation of compounds 12p,
13e, 14e, and 15e
(b), 1654, 1577, 1541; H NMR (300 MHz, CD3OD): d
1.06 (t, J=7.3 Hz, 3H), 1.82±1.99 (m, 3H), 2.31±2.42 (m,
1H), 2.95±3.01 (m, 2H), 3.12±3.42 (m, 5H), 3.60±3.65
(m, 1H), 3.77±3.96 (m, 3H), 7.07±7.18 (m, 4H), 7.49 (dd,
J=6.9 Hz, 6.9 Hz, 2H), 7.58 (t, J=7.3 Hz, 1H), 7.92 (d,
J=7.0 Hz, 2H); 13C NMR (75 MHz, CD3OD): d 10.6,
18.9, 24.2, 28.5, 29.7, 37.0, 52.2, 53.8, 61.1, 126.7, 127.1,
127.9, 128.9, 129.1, 129.6, 132.7, 133.4, 135.3, 171.1; MS
(CI with NH3): m/z (rel. intensity) 202 (14), 337 (100,
The method adopted for the synthesis of 5-hydroxy-2-
[N-(2-benzamidoethyl)-N-n-propylamino]tetralin hydro-
chloride (12p) is described: under a nitrogen atmo-
sphere, a 1 M solution of BBr3 in CH2Cl2 (2 mL,
4 mmol) was added dropwise to a solution of the free
base of 12a (0.25 g, 0.7 mmol) in CH2Cl2 which was
cooled at 50 ꢀC. Stirring was continued at 50 ꢀC for
1 h, and then the reaction mixture was allowed to gra-
dually warm to room temperature. After stirring over-
night at room temperature, the reaction mixture was
concentrated under reduced pressure and the residue
was partitioned between CH2Cl2 and saturated aqueous
NaHCO3 solution. The organic solution was dried
(Na2SO4), ®ltered and evaporated to dryness, which
gave the crude phenol as a brown oil. Puri®cation by
column chromatography yielded 0.21 g (0.6 mmol) of
the pure base of 12p as a colourless oil, which was con-
verted to the hydrochloride salt.
.
M+1); Anal. (C22H28N2O HCl ˆH2O) C, H, N.
.
2-{N-[2-(2,3-Dimethoxy)benzamidoethyl]-N-n-propyl-
amino}tetralin oxalate (16b). Method A. Yield 25%;
mp 70±72 ꢀC; IR: cm 3360 (b), 2936, 2835, 2619 (b),
1
2520 (b), 1719, 1649, 1577, 1524; 1H NMR (base,
200 MHz, CDCl3): d 0.90 (t, J=7.3 Hz, 3H), 1.45±1.71
(m, 3H), 1.98±2.10 (m, 1H), 2.55 (dd, J=7.5 Hz, 7.5 Hz,
2H), 2.76±3.04 (m, 7H), 3.52±3.60 (m, 2H), 3.92 (s, 3H),
3.93 (s, 3H), 7.02±7.09 (m, 5H), 7.16 (t, J=7.9 Hz, 1H),
7.73 (dd, J=7.2 Hz, 1.8 Hz, 1H), 8.39 (bs, 1H); 13C
NMR (base, 50 MHz, CDCl3): d 11.9, 22.3, 25.9, 29.9,
31.9, 38.5, 49.0, 52.4, 56.1, 56.7, 61.3, 115.1, 122.8,
124.2, 125.6, 125.7, 127.1, 128.6, 129.4, 136.3, 147.7,
152.5, 165.1; MS (CI with NH3): m/z 190 (16), 202 (6),
5-Hydroxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]-
tetralin hydrochloride (12p). Yield 87%; mp 116±
118 ꢀC; IR: cm 3231 (b), 2966, 2623 (b), 1654, 1588,
1
397 (100, M+1); Anal. (C24H32N2O3 C2H2O4 ˆH2O)
C, H, N.
1534; 1H NMR (base, 200 MHz, CDCl3): d 0.91 (t,
J=7.3 Hz, 3H), 1.47±1.60 (m, 3H), 1.99±2.05 (m, 1H),
.
.

2124
E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
2.48±2.60 (m, 3H), 2.78±3.02 (m, 6H), 3.47±3.58 (m,
2H), 6.64 (dd, J=19.2 Hz, 7.7 Hz, 2H), 6.94 (t,
J=7.6 Hz, 1H), 7.40±7.52 (m, 3H), 7.79±7.83 (m, 2H);
13C NMR (base, 50 MHz, CDCl3): d 11.6, 21.6, 23.4,
25.2, 31.8, 37.8, 48.2, 52.1, 55.9, 112.0, 120.8, 123.1,
126.2, 126.8, 128.5, 131.4, 134.2, 137.4, 154.1, 167.7; MS
(CI with AcOH): m/z 353 (M+1); Anal. (C22H28N2O2
Research, Oregon Health Sciences University, Portland,
OR) and Chinese hamster ovary (CHO) cells expressing
human dopamine D3 receptors (obtained from
INSERM Institute, Paris, France) were grown and the
cell membranes were prepared essentially as described
by Malmberg et al.48 Brie¯y, the Ltk cells were cul-
tured in DMEM (Dulbecco's Modi®ed Eagles Medium)
supplemented with 10 mM HEPES, 10% fetal calf
serum (FCS, heat-inactivated) and selected with G-418
(Geneticin 0.7 mg/ml). CHO cells were grown in
DMEM supplemented as above, except that the FCS
was dialyzed and MEM Amino Acids solution (50Â)
without l-glutamine was added. The cells were detached
with 0.05% trypsin and 0.02% EDTA, centrifuged
(300Âg, for 10 min), washed twice with DMEM and
homogenized in 10 mM Tris-HCl and 5 mM MgSO4
(pH 7.4). The homogenate was washed (43,500Âg, for
10 min) in binding bu€er (50 mM Tris-HCl, 120 mM
NaCl, 5 mM KCl, 1.5 mM CaCl2, 4 mM MgCl2, 1 mM
EDTA, pH 7.4) and stored at 70 ꢀC until further use.
On the day of the experiment the frozen homogenate
was thawed, homogenized with a Branson 450 soni®er
and suspended in binding bu€er. The binding assays
were performed in a total volume of 0.5 mL with a
receptor concentration of about 100 pM (ꢁ30 mg pro-
tein/0.5 mL). 1 nM [3H]-Raclopride (Kd's for dopamine
D2A and D3 1.20 and 1.60 nM, respectively; speci®c
activity 80 Ci/mmol, Du Pont New England Nuclear,
Boston, MA, or 41 Ci/mmol, Astra Arcus AB, Soder-
talje, Sweden) was incubated with the test compound
(10±12 concentrations) at 22 ꢀC for 1 h. Binding in the
presence of 1 mM (+)-butaclamol (Research Bio-
chemicals Inc., Natick, MA) was de®ned as nonspeci®c.
The incubation was terminated by rapid ®ltration
through Whatman GF/B glass®ber ®lters and sub-
sequent washing with ice-cold bu€er, using a Brandel
cell harvester. Scintillation cocktail (Packard Ultima
Gold, 4 mL) was added and the radioactivity was deter-
mined with a Liquid Scintillation Counter (Packard
2200CA or 2500TR) at about 50% eciency. Alter-
natively, the incubation was terminated by rapid ®ltra-
tion through Wallac Printed Filtermat B and washed
with cold bu€er using a Tomtec harvester, and the
radioactivity was determined in 205 Beta Plate (Wallac),
with about 30% eciency. Protein concentration was
measured by the method of Markwell et al.50
.
.
HCl H2O) C, H, N.
6-Hydroxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]-
tetralin hydrochloride (13e). Yield 89%; mp 108±110 ꢀC;
1
1
IR: cm 3244 (b), 2939, 2629 (b), 1654, 1577, 1534; H
NMR (base, 200 MHz, CDCl3): d 0.90 (t, J=7.3 Hz,
3H), 1.37±1.61 (m, 3H), 1.90±1.95 (m, 1H), 2.52±2.98
(m, 9H), 3.45±3.55 (m, 2H), 6.59±6.66 (m, 2H), 6.82±
6.86 (m, 1H), 7.31 (bs, 1H), 7.40±7.52 (m, 3H), 7.82 (m,
2H); 13C NMR (base, 50 MHz, CDCl3): d 11.6, 21.4,
25.4, 29.4, 30.7, 37.7, 48.4, 52.2, 56.5, 113.3, 114.8,
126.6, 126.8, 128.5, 130.1, 131.4, 134.1, 137.0, 154.5,
167.6; MS (CI with NH3): m/z 353 (M+1); Anal.
3
.
(C22H28N2O2 HCl
.
4
H2O) C, H, N.
7-Hydroxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]-
tetralin hydrochloride (14e). Yield 94%; mp 111±113 ꢀC;
1
IR: cm 3236 (b), 2938, 2627 (b), 2513 (b), 1647, 1577,
1536; 1H NMR (200 MHz, CD3OD):
d 0.98 (t,
J=7.3 Hz, 3H), 1.87±2.13 (m, 3H), 2.52±2.60 (m, 1H),
2.76±2.85 (m, 3H), 3.03±3.16 (m, 1H), 3.24±3.42 (m,
4H), 3.62±4.00 (m, 4H), 6.50±6.65 (m, 2H), 6.88 (d,
J=8.1 Hz, 1H), 7.43±7.57 (m, 3H), 8.14±8.19 (m, 2H);
13C NMR (50 MHz, CD3OD): d 11.3, 18.8, 24.0, 24.8,
28.1, 36.5, 52.5, 54.7, 61.4, 114.9, 116.0, 126.3, 128.4,
129.1, 130.2, 132.2, 134.5, 134.8, 156.4, 167.2; MS (CI
with NH3): m/z 353 (M+1); Anal. (C22H28N2O2
.
.
HCl ‰H2O) C, H, N.
8-Hydroxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]-
tetralin hydrochloride (15e). Yield 74%; mp 116±
119 ꢀC; IR: cm 3215 (b), 2968, 2937, 2615 (b), 2515
1
(b), 1654, 1588, 1635; 1H NMR (300 MHz, CDCl3): d
0.92±0.96 (m, 3H), 1.71±1.93 (m, 2H), 2.20±2.30 (m,
3H), 2.47±2.77 (m, 3H), 3.12±3.54 (m, 7H), 3.78±3.94
(m, 2H), 6.43±6.45 (m, 1H), 6.78±6.89 (m, 2H), 7.38±
7.53 (m, 3H), 8.01±8.09 (m, 2H); 13C NMR (75 MHz,
CDCl3): d 11.1, 18.0, 24.1, 28.1, 36.4, 51.5, 53.9, 55.2,
61.6, 112.7, 118.7, 119.7, 127.2, 127.6, 128.6, 132.0,
132.6, 135.6, 154.5, 168.7; MS (CI with NH3): m/z 353
3
[3H]-8-OH-DPAT Binding to serotonin 5-HT1A receptors.
This assay was performed essentially as previously
described by Hedberg et al.51 Brie¯y, male Sprague-
Dawley rats weighing 150±220 g (B & K Universal
AB, Sollentuna, Sweden) were decapitated and the hip-
pocampi were dissected out on ice. The tissue was
homogenized at 0 ꢀC using an Ultra-Turrax, in 50 mM
Tris-HCl bu€er containing 10 mM EDTA (pH 7.4). The
homogenate was centrifuged at 4 ꢀC for 10 min at
.
(M+1); Anal. (C22H28N2O2 HCl
calcd, 6.96; found, 6.42.
.
4
H2O) C, H; N:
Pharmacology
[3H]-Raclopride binding to cloned dopamine D2A and D3
receptors. Mouse ®broblast (Ltk ) cells expressing
human dopamine D2A receptors (obtained from Dr. O.
Civelli, Vollum Institute for Advanced Biomedical

E. J. Homan et al./Bioorg. Med. Chem. 6 (1998) 2111±2126
2125
17,000Âg, the pellet was resuspended in 50 mM Tris-
HCl with 10 mM EDTA and recentrifuged. The ®nal
pellet was frozen in 0.32 M sucrose and stored at 70 ꢀC
until further use. On the day of the experiment the fro-
zen homogenate was thawed and suspended in binding
bu€er containing 50 mM Tris-HCl, 2 mM CaCl2, 1 mM
MgCl2 and 1 mM MnCl2 (pH 7.4), to a ®nal concentra-
tion of 2.0 mg original wet weight per 0.5 mL. In order
to remove endogenous serotonin the membranes were
preincubated for 10 min at 37 ꢀC and subsequently
10 mM pargyline was added. Competition experiments
with 1 nM [3H]-8-OH-DPAT (Kd=1.00 nM; speci®c
activity 136, 149 or 163 Ci/mmol, Du Pont New Eng-
land Nuclear, Boston, MA) and test compounds (10±12
concentrations) were performed at 37 ꢀC for 45 min.
Nonspeci®c binding was de®ned with 100 mM 5-HT
(Sigma Chemical Co., St. Louis, MO). The incubations
were terminated and the radioactivity was determined as
described for the dopamine receptor binding assay.
8. Invernizzi, R. W.; Cervo, L.; Samanin, R. Neuropharmacol-
ogy 1988, 27, 515.
9. McMillen, B. A.; Scott, S. M.; Davano, E. A. J. Pharm.
Pharmacol. 1988, 40, 885.
10. Hicks, P. B. Life. Sci. 1990, 47, 1609.
11. Neal-Beliveau, B. S.; Joyce, J. N.; Lucki, I. J. Pharmacol.
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12. Wadenberg, M. L.; Ahlenius, S. J. Neural Transm. Gen.
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13. Wadenberg, M. L.; Ahlenius, S. J. Neural. Transm. 1988,
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G. C. J. Med. Chem. 1996, 39, 4692.
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Blum, P. S.; Codd, E. E.; Kukla, M. J.; Malloy, E.; Maryano€,
B. E.; Maryano€, C. A.; Ortegon, M. E.; Rasmussen, C. R.;
Reitz, A. B.; Renzi, M. J.; Schwender, C. F.; Shank, R. P.;
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17. Reitz, A. B.; Baxter, E. W.; Bennett, D. J.; Codd, E. E.;
Jordan, A.; Malloy, E. A.; Maryano€, B. E.; McDonell, M. E.;
Ortegon, M. E.; Renzi, M. J.; Scott, M. K.; Shank, R. P.;
Sherrill, R. G.; Vaught, J. L.; Wustrow, D. J. J. Med. Chem.
1995, 38, 4211.
Data analysis
The Ki values (inhibition constants) of the test com-
pounds were determined from inhibition curves using
the iterative non-linear curve-®tting program
LIGAND.52 One- and two-site curve ®tting was tested
in all experiments. The one-site model gave a better ®t
(p>0.05; F test) unless otherwise stated. The Kd values
(dissociation constants) of the various radioligands used
to calculate the Ki values were determined by saturation
studies.
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