New σ and 5-HT(1A) receptor ligands: ω-(tetralin-1-yl)-n-alkylamine derivatives

Article abstract of DOI:10.1021/jm950409c

Two series of compounds that are structurally related to benzomorphans, derived by structural modification of arylpiperazines with high 5-HT(1A) affinity and moderate σ affinity, were prepared in order to increase σ affinity and selectivity. All new compo

Full text of DOI:10.1021/jm950409c

1
76
J . Med. Chem. 1996, 39, 176-182
New σ a n d 5-HT1A Recep tor Liga n d s: ω-(Tetr a lin -1-yl)-n -a lk yla m in e Der iva tives
Francesco Berardi,* Nicola A. Colabufo, Giuseppe Giudice, Roberto Perrone,* and Vincenzo Tortorella
Dipartimento Farmaco-chimico, Universit a` di Bari, via Orabona, 4, 70126 Bari, Italy
Stefano Govoni and Laura Lucchi
Istituto di Scienze Farmacologiche, Universit a` di Milano, via Balzaretti, 9, 20133 Milano, Italy
X
Received J une 6, 1995
Two series of compounds that are structurally related to benzomorphans, derived by structural
modification of arylpiperazines with high 5-HT1A affinity and moderate σ affinity, were prepared
in order to increase σ affinity and selectivity. All new compounds are N-substituted-ω-(1,2,3,4-
tetrahydronaphthalen-1-yl)- or -ω-(1,2-dihydronaphthalen-4-yl)-n-alkylamines with, in some
cases, a methoxy group on the tetralin moiety. They were tested in radioligand binding assays
3
3
on σ ([ H]DTG and [ H]-(+)-pentazocine), D-2 dopaminergic, 5-HT1A and 5-HT
2
serotonergic,
and PCP (phencyclidine) receptors. A first set of compounds bearing a 4-(1-substituted)pipera-
zine moiety as terminal fragment on the alkyl chain showed moderate to high σ affinity (K
i
)
5
.3-139 nM), the most active and selective being 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-
2 i
tetrahydronaphthalen-1-yl)-n-propyl]piperazine (14), with probable pronounced σ affinity (K
3
3
)
1
i
5.3 nM on [ H]DTG and K ) 71 nM on [ H]-(+)-pentazocine). Moreover, compound 13, a
-benzylpiperazine analogue of 14, preserved a dual high 5-HT1A and σ affinity (K
on [ H]-5-HT and K
i
) 3.6 nM
3
3
i
) 7.0 nM on [ H]DTG). The second set of compounds includes some
N-phenylalkyl derivatives of 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propylamine
that can be considered to be open-chain derivatives of 4-substituted-1-arylpiperazines. Among
these compounds that had a lower activity toward σ binding sites, a high 5-HT1A affinity was
found for the N-(3-phenylpropyl) derivative 21 (K
selectivity.
i
) 4.4 nM) which demonstrated very good
values ranging from 10- to 10-7 M, no σ SAR study was
8
In tr od u ction
possible.
The traditional antipsychotic therapy by D-2 antago-
nists causes extrapyramidal symptoms (EPS) or tardive
diskinesia (TD). In order to avoid these side effects,
1
some atypical antipsychotic drugs such as clozapine,
remoxipride, and risperidone have been proposed, as
these have alternative modes of action. Among these,
activity of the σ receptor seems to hold hopeful pros-
2
,3
pects.
In recent years, the σ binding sites have been dem-
4
onstrated to be distinct from opioid receptors and from
the PCP/NMDA (phencyclidine/N-methyl-D-aspartate)
5
,6
receptor complex, but the biological function of puta-
7
tive σ receptors remains unknown, and no endogenous
σ neurotransmitter has been identified.4 For this reason
σ sites are more correctly identified as binding sites than
receptors. At the moment three σ site subtypes are
8
9,10
recognized, namely σ1, σ2, and more recently σ3,
and
several SARs (structure-activity relationships) have
been developed in order to find structural determinants
for characterizing σ binding sites.1
1-15
Starting from haloperidol (1), a nonselective σ ligand,
several piperidine and piperazine derivatives have been
1
6,17
18,19
developed
and reported as selective σ ligands.
Moreover, structures such as BMY 14802 (2) and
cinuperone (3) entered clinical trials for treatment of
central nervous system (CNS) disorders,3 but they
present a nonselective binding profile such that an
understanding of their clinical behavior is difficult.
Recently we reported20 multireceptorial binding
data for a series of 1-aryl-4-(1-tetralinyl)-n-propylpip-
erazines (4) that demonstrated high 5-HT1A serotonergic
affinity. In that study, σ receptor binding assays were
carried out, and as all tested compounds showed IC50
*
To whom correspondence should be addressed.
Abstract published in Advance ACS Abstracts, November 1, 1995.
X
0
022-2623/96/1839-0176$12.00/0 © 1996 American Chemical Society

New σ and 5-HT1A Receptor Ligands
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 177
Sch em e 1a
a
Reagents: (A) H2, 10% Pd/C; (B) HCl.
Ta ble 1. Physical Properties for 11-19
compd
R
R1
R2
R3
n
formulaa
mp, °C
recryst solv
1
1
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
A
A
B
B
B
B
B
B
B
H
H
H
H
H
OCH3
H
OCH3
H
H
CH2Ph
CH2Ph
CH2Ph
cyclohexyl
2-THPb
2-THPb
2-THPb
H
1
1
1
1
1
1
2
1
1
C24H30N2‚2HCl
243-245
262-264
267-269
256-258
273-275
243-245
264-266
273-275
235-237
MeOH
MeOH
MeOH
MeOH/Et2O
MeOH/Et2O
MeOH/Et2O
MeOH/Et2O
MeOH/Et2O
MeOH/Et2O
OCH3
OCH3
OCH3
H
H
OCH3
H
C25H32N2O‚2HCl‚H2O
C25H34N2O‚2HCl 1
C24H38N2O‚2HCl‚ /2H2O
C22H33N3‚2HCl‚H2O
1
C23H35N3O‚2HCl‚ /3H2O
C24H37N3O‚3HCl
C18H28N2O‚2HCl‚H2O
1
OCH3
H
C18H28N2O‚2HCl‚ /3H2O
a
C, H, and N analyses were within (0.4% of the theoretical values for the formulas given. b 2-THP ) 2-(3,4,5,6-tetrahydropyridyl).
Ta ble 2. Physical Properties for 20-23
Furthermore, all tested 1-arylpiperazines showed poor
σ selectivity profile versus dopamine and serotonin
receptors, whereas better selectivity was achieved by
eliminating the N-aryl substituent.
In fact 1-[3-(1,2-dihydro-6-methoxynaphthalen-4-yl)-
n-propyl]piperazine (4a : 6-OCH3, Ar ) H), which had
2
1
compd
R
formulaa
mp, °C
195-197 MeOH/Et2O
136-137 CHCl3/Et2O
122-126 MeOH/Et2O
111-113 CHCl3/Et2O
recryst solv
been reported to be inactive toward 5-HT1A, 5-HT2, and
D-2 receptors, was subsequently tested in new binding
20
21
NHPh
CH2Ph
Ph
C22H30N2O‚2HCl
C23H31NO‚HCl
C22H29NO‚HClc
C26H35NO‚HCl
2
2
assays and, although a striking σ affinity value was
not observed, an undoubted σ selectivity was neverthe-
less evident.
2
2
2
3
THNb
a
Analyses for C, H, N. b THN ) 1-(1,2,3,4-tetrahydronaphtha-
With these findings as a starting point, in an effort
to contribute to defining the structural requirement for
binding to the σ receptor and to discover highly selective
σ ligands, two series of compounds deriving from
arylpiperazines 4 were prepared (Scheme 1) and tested.
In the first set, the aryl substituent was modified or
eliminated (Table 1), and in the second one the pipera-
zine ring was opened (Table 2).
lenyl). c H: calcd, 8.76; found, 9.21.
In particular the tetralin nucleus of arylpiperazines
4 underwent limited changes, since it is present in
benzomorphan structures, like σ ligand (+)-pentazocine
(5), whereas the N-1-phenyl substituent was replaced
by a N-benzyl (11-13) or reduced to a cyclohexyl (14);
similarly N-1-(2-pyridyl) derivatives were partially hy-

1
78 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Berardi et al.
Ta ble 3. Binding Affinities and Selectivities
Ki, nMa
σ
Ki ratio
5
-HT1A
PCP
[ H]PCP
3
b
3
compd
[3H]DTG
[3H]-(+)-pentazocine
[ H]-5-HT
5-HT1A/σ
PCP/σ
1
1
1
1
1
1
1
1
1
2
2
2
2
1
2
3
4
5
6
7
8
9
0
1
2
3
66
139
7.0
5.3
43.8
29
46.5
270
>877
265
214
>1430
3.6
8430
98%c
3890
3.2
>10
0.5
5.4
1
14
0.8
>5
128
25.7
71
111
556
>17400
28.6
44.2
414
37.1
>92600
94%c
91%c
396
8330
>1430
>1430
14.1
79%c
80%c
2130
0.05
0.03
0.2
8
164
128
152
159
469
4.4
31.4
22.8
25000
20400
100%c
0.05
cimetidine
scopolamine
DTG
inactive
inactive
37.3
4.2
haloperidol
10
8
-OH-DPAT
4.3
SKF10047
370
a
Data had (SEM < 5% of mean values. In the presence of 10-6 M ketanserin as 5-HT2 blocker. c Data expressed as percent inhibition
b
-
5
at concentration of 10 M.
drogenated to 2-(3,4,5,6-tetrahydropyridyl) derivatives
P h a r m a cology
(
15-17); two compounds (18 and 19) were N-4-unsub-
The compounds 11-23 were evaluated for in vitro
activity on σ, serotonin 5-HT1A and 5-HT2, PCP (phen-
cyclidine), and dopamine D-2 receptors by radioreceptor
binding assays. All of the compounds were used in the
form of hydrochloride salts. The following specific
stituted to explore the true importance of 1,4-disubsti-
tution of piperazine, even in reduced tetralinylalkyl
derivatives. Opening the piperazine ring in N-phe-
nylpiperazines 4 led to the phenylaminoethyl derivative
2
0 and its isosteric analogue 21, of which compound 22
ligands and tissue sources were used. (a) σ receptors:
was a lower homologue. Finally, compound 23 was
chosen as a semirigid derivative of 21.
3
[
H]DTG (1,3-di-o-tolylguanidine), guinea pig brain
3
cortex membranes. (b) σ1 receptors: [ H]-(+)-pentazo-
cine, whole rat brain membranes. (c) Serotonin 5-HT1A
receptors: [ H]serotonin, rat hippocampus membranes.
d) Serotonin 5-HT2 receptors: [ H]ketanserin, rat brain
cortex membranes. (e) PCP receptors: [ H]phencycli-
dine, rat hippocampus membranes. (f) Dopamine D-2
receptors: [ H]spiroperidol, rat striatal membranes.
Ch em istr y
3
3
(
All final compounds were synthesized by Grignard
reactions starting from 1-tetralone or methoxy-1-tetral-
ones. The respective key intermediates of compounds
3
3
1
1-16 and 18-23, the 4-(3-bromo-n-propyl)-1,2-dihy-
The following cold compounds were used as reference
to define specific binding: (a) DTG, (b) haloperidol (see
methods), (c) 8-OH-DPAT in the presence of a saturating
ketanserin concentration, (d) ketanserin, (e) (+)-N-
allylnormetazocine (SKF10,047), (f) (+)-butaclamol.
Concentrations required to inhibit 50% of radioligand
dronaphthalenes 7a -c (Scheme 1) were obtained as
previously described,21 whereas compound 17 (Table 1)
was prepared in the same way as compounds 15 and
1
thalene. Dihydronaphthalene derivatives 11 and 12
were obtained from 7a and 7c, respectively, as previ-
ously reported for arylpiperazines. Tetralin deriva-
6, via 4-(4-chloro-n-butyl)-8-methoxy-1,2-dihydronaph-
2
0
2
1
specific binding (IC ) were determined by two to three
50
independent experiments with samples in triplicate and
tives 13 and 14 were prepared by the same reaction
from 3-(bromopropyl)tetralin 8c20 as were the 1-(2-
six to nine different concentrations of the drug studied.
The specific binding, defined as described above in the
Pharmacological Methods, represented more than 70%
of the total binding. The Bmax and Kd values used to
pyridyl)piperazine derivatives 9a ,b from dihydronaph-
thalenes 7a ,b. Subsequent catalytic hydrogenation of
1
-(2-pyridyl)piperazines 9a ,b as hydrochloride salts led
2
6
feed the Cheng-Prusoff equation to calculate Ki were
calculated from saturation experiments using the latest
version of the Ligand computerized program as origi-
to the doubly reduced tetralinyltetrahydropyridyl com-
pounds 15 and 16. The exact structures of these
derivatives, in particular with reference to the position
of the double bond, were confirmed by COSY experi-
ments. Monosubstituted piperazines 18 and 19 were
afforded by hydrolysis of N-acetyl derivatives 10b,c,
respectively, that were derived from 8b,c as already
reported21 for a corresponding unsaturated compound.
Finally, amines 20-23 were prepared in the usual way
from 8c with appropriate commercially available amines,
except for 2-(1,2,3,4-tetrahydronaphthalen-1-yl)ethy-
2
7
nally described by Munson and Rodbard.
Resu lts a n d Discu ssion
All 1,4-disubstituted piperazine derivatives (11-17)
demonstrated moderate to high σ affinity (Table 3), their
Ki reaching nanomolar range (Ki ) 5.3-139 nM),
superior than the DTG value for compounds 13 and 14
i
(K ) 7.0 and 5.3 nM, respectively). Compared with the
2
3
20
lamine which was synthesized by reducing the corre-
sponding nitrile with LiAlH4, as for the arylpiperazine
analogue.
corresponding 1-phenylpiperazine derivatives, the re-
2
4
placement of a phenyl with a cyclohexyl or a benzyl
group in the above compounds attained enhanced σ
2
5

New σ and 5-HT1A Receptor Ligands
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 179
affinity whereas (1,2-dihydronaphthalen-4-yl)-n-propy-
lpiperazines 11 and 12 failed in that respect.
No satisfactory improvements were obtained by re-
ducing the 2-pyridyl group to a 2-(3,4,5,6-tetrahydro-
pyridyl) ring (15-17).
Additional changes in structure, such as lengthening
of the intermediate chain (17) or methoxyl group
displacement (16) or its disappearance (15) from the
tetralin moiety, did not produce significant variations
in affinity.
presence of a chiral center in the tetralin ring of such
compounds, further stereochemical investigations are
needed on the enantiomers, in order to clarify the exact
classification of these compounds as σ ligands. Finally,
compound 21 is noteworthy for its good 5-HT1A affinity
and its excellent selectivity, although its template is
quite different from an arylpiperazine.
Exp er im en ta l Section
Ch em istr y. Column chromatographies were performed
with 1:30 Merck silica gel 40 (0.063-0.200 mm) as the
stationary phase. Melting points were determined in open
capillaries on a Gallenkamp electrothermal apparatus. El-
emental analyses were performed by the Microanalytical
Section of our department on solid samples only; the analytical
However, an additional lipophilic group was needed
as substituent on the piperazine N-1 position, since the
unsubstituted N-1 derivatives 18 and 19 showed low σ
affinity, neither being better than the corresponding
unsaturated derivative 4a (6-OCH3, Ar ) H).
Opening the piperazine ring (20-23) represents a
crucial alteration, probably because of the loss of
tertiary nitrogen and of a cyclic spacer: compound 20
showed a lower affinity than the corresponding arylpip-
erazine derivative.
results (C, H, N) were within (0.4% of the theoretical values
unless otherwise stated. 1H NMR spectra were recorded either
on a Varian XL-200 (when indicated) or on a Bruker AM 300
WB instrument. The latter was also used for decoupling
spectra and carrying out COSY experiments. Chemical shifts
are reported in parts per million (ppm, δ). Recording of mass
spectra was done on an HP 5995C gas chromatograph/mass
spectrometer, electron impact 70 eV, equipped with an HP
3
Because of a nondiscriminant behavior by [ H]DTG
among σ1 and σ2 subtypes of binding sites, an additional
5
9970A workstation. All compounds had NMR and mass
3
σ1 assay was carried out versus [ H]-(+)-pentazocine for
spectra that were fully consistent with their structure. All of
the spectral data of amines refer to their free bases.
Am in a t ion of (3-Br om op r op yl)h yd r on a p h t h a len es.
Gen er a l P r oced u r e To Obta in Com p ou n d s 9a ,b, 10b,c,
more σ active compounds (13 and 14). Results showed
nearly preferential σ2 affinity, in particular the (+)-
pentazocine/DTG ratio was >10 for compound 14.
Another aim of the study was to describe selectivity
versus dopamine and serotonin receptors. All tested
1
1-14, a n d 20-23. The 1-(3-bromopropyl)-1,2,3,4-tetrahy-
dronaphthalene derivative (7a -c) or the 4-(3-bromopropyl)-
,2-dihydronaphthalene derivative (8b,c) (3.5 mmol) was
1
3
compounds weakly displaced [ H]spiroperidol on the D-2
refluxed in DMF (20 mL) with an equimolar amount of the
appropriately substituted piperazine or amine and sodium
carbonate. Working up was carried out as previously de-
scribed.21 The crude residue was chromatographed on a silica
gel column (CHCl /CH OH, 95:5, as eluent, unless otherwise
3 3
indicated) and the final compounds were obtained as an almost
colorless to pale yellow oil.
dopaminergic receptor, compounds 11 and 23 having a
Ki of 732 and 849 nM, respectively, and the remainder
(
12-22) a Ki of more than 1850 nM while the reference
compound butaclamol had Ki ) 0.3 nM. When such
results are considered, σ affinity may be explained on
the basis of the spatial similarity between 1-phenyl-2-
aminopropane, the primary pharmacophore proposed for
benzomorphans by Glennon and co-workers,2 and the
side chain of compounds 13 and 14 if it is considered to
be folded on itself (6), like in the template of the
octahydrobenzoquinolines.13 Moreover, the absence of
a 1-phenyl-2-aminoethane moiety as in haloperidol (1)
may explain the lack of D-2 affinity.
1
-(2-P yr id yl)-4-[3-(1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
n -p r op yl]p ip er a zin e (9a ). 9a was prepared from 7a and
8
1
1
3
-(2-pyridyl)piperazine and eluted with CHCl (75% yield): H
NMR (CDCl ) 1.71-1.81 (mm, 2H, CH CH CH N), 2.21-2.26
3
2
2
2
(mm, 2H, endo CH
2
), 2.42-2.56 [mm, 8H, CH
2
2 2
CH CH N and
CH N(CH ) ], 2.72 (t, 2H, J ) 8.0 Hz, benzyl CH ), 3.53 [t,
2
2 2
2
4
8
+
H, J ) 5.1 Hz, (CH
2
)
2
N], 5.86 (t, 1H, J ) 4.5 Hz, vinyl), 6.57-
+
+
.18 (mm, 8H, aromatic); GC/MS m/z 335 (M + 2, 2), 334 (M
+
1, 13), 333 (M , 52), 226 (35), 214 (40), 121 (29), 107 (100).
3
Similar results were derived from [ H]ketanserin
1
-Acetyl-4-[3-(7-m eth oxy-1,2,3,4-tetr ah ydr on aph th alen -
binding on the 5-HT2 serotonin receptor for all tested
1
-yl)-n -p r op yl]p ip er a zin e (10b). The title compound was
1
compounds (Ki > 2600 nM, ketanserin, Ki ) 34 nM).
obtained from 8b and 1-acetylpiperazine with a 93% yield: H
3
NMR (200 MHz, CDCl ) 1.45-1.90 [mm, 8H, CH(CH CH ) ],
With regard to the [ H]-5-HT binding, the tissue
3
2
2 2
2
2
.10 (s, 3H, CH
.88 (mm, 3H, benzylic), 3.38-3.72 [mm, 4H, (CH )
2 2
3
), 2.26-2.54 [mm, 6H, CH
2
N(CH
2 2
) ], 2.60-
chosen and the definition of specific binding with 8-OH-
DPAT suggest an interaction with 5-HT1A sites. In this
assay some compounds (11, 13-15, and 17) presented
a dual σ/5-HT1A affinity, whereas non-piperazine com-
pounds 20, 21, and 23 demonstrated quite a selective
NCO], 3.81
(
(
3
s, 3H, OCH ), 6.60-7.10 (mm, 3H, aromatic); GC/MS m/z 332
+
+
+
M
+ 2, 1), 331 (M + 1, 6), 330 (M , 26), 141 (100), 128 (22),
9 (24).
-Acetyl-4-[3-(5-m eth oxy-1,2,3,4-tetr ah ydr on aph th alen -
9
1
5
-HT1A profile.
Moreover, the compounds with highest σ affinity (13
1-yl)-n -p r op yl]p ip er a zin e (10c). 10c was prepared from 8c
and 1-acetylpiperazine with 86% yield: H NMR (200 MHz,
1
3
CDCl
.22-2.98 [mm, 9H, CH
mm, 4H, (CH NCO], 3.82 (s, 3H, OCH
3
3
) 1.48-1.88 [mm, 8H, CH(CH
2
CH
and benzylic], 3.38-3.72
), 6.60-7.28 (mm,
2 2 3
) ], 2.10 (s, 3H, CH ),
and 14) showed a high Ki value for [ H]PCP (phencyc-
lidine) binding, so that quite a good selectivity versus
the PCP receptor was evident. That is in agreement
with the receptorial model that discriminates σ binding
sites from the PCP site on the basis of an additional
2
[
2
N(CH
2 2
)
2
)
2
+
+
3
3
H, aromatic); GC/MS m/z 332 (M + 2, 1), 331 (M + 1, 8),
+
30 (M , 33), 141 (100), 128 (22), 99 (31).
-Ben zyl-4-[3-(1,2-d ih yd r on a p h th a len -4-yl)-n -p r op yl]-
p ip er a zin e (11). Starting from 7a and 1-benzylpiperazine,
1
1
4
lipophilic site.
1
1
1 was obtained with 95% yield, after elution with CHCl
NMR (CDCl ) 1.66-1.76 (mm, 2H, CCH CH CH N), 2.20-2.25
mm, 2H, CdCHCH ), 2.37-2.68 (mm, 12H, piperazine and
CCH CH CH N), 2.71 (t, 2H, J ) 8.0 Hz, benzylic), 3.49 (s,
H, NCH Ph), 5.84 (t, 1H, J ) 4.5 Hz, vinyl CH), 7.10-7.31
(mm, 9H, aromatic); GC/MS m/z 348 (M + 2, 2), 347 (M + 1,
17), 346 (M , 68), 255 (36), 128 (25), 91 (100).
3
: H
It may be concluded that for phenylpiperazines,
compounds with high 5-HT1A affinity, a replacement of
an aryl with a benzyl group, or rather, with a cyclohexyl
group, leads to a probable slightly selective σ2 ligand
3
2
2
2
(
2
2
2
2
2
2
(
14) or to a mixed σ/5-HT1A affinity compound with a
+
+
+
D-2 and PCP selective profile (13). Because of the

1
80 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Berardi et al.
1
1
-Ben zyl-4-[3-(1,2-d ih yd r o-8-m eth oxyn a p h th a len -4-yl)-
n -p r op yl]p ip er a zin e (12). The title compound was prepared
from 7c and 1-benzylpiperazine and eluted with CHCl (72%
CH N),
), 2.36-2.47 (mm, 12H, pip-
N), 2.71 (t, 2H, J ) 8.2 Hz, benzylic),
Ph), 3.81 (s, 3H, OCH ), 5.84 (t, 1H, J ) 4.5
in quantitative yield as a colorless oil: H NMR (CDCl
1.88 [mm, 12H, CdNCH CH CH and CH(CH CH ], 2.14 (t,
2H, NdCCH ), 2.27-2.67 [mm, 6H, CH N(CH ], 2.71-2.74
(mm, 3H, benzylic), 3.29 [t, 4H, J ) 5.1 Hz, (CH NC], 3.48
3
) 1.50-
2
2
2
2
2 2
)
3
2
2
2 2
)
1
yield). H NMR (CDCl
.14-2.25 (mm, 2H, CdCHCH
erazine and CCH CH CH
.51 (s, 2H, NCH
3
) 1.60-1.74 (mm, 2H, CCH
2
CH
2
2
2 2
)
2
2
(t, 2H, J ) 5.7 Hz, CdNCH ), 7.00-7.24 (mm, 4H, aromatic);
GC/MS m/z 341 (M + 2, 1), 340 (M + 1, 2), 339 (M , 9), 241
2
+
+
+
2
2
2
3
2
3
(21), 228 (19), 124 (33), 111 (100).
4
Hz, vinyl CH), 6.74-7.38 (mm, 8H, aromatic); GC/MS m/z 378
-[3-(7-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-n -
p r op yl]-1-[2-(3,4,5,6-tetr a h yd r op yr id yl)]p ip er a zin e (16).
+
+
+
(
M
+ 2, 4), 377 (M + 1, 27), 376 (M , 100), 285 (35), 189
34), 91 (46).
-Ben zyl-4-[3-(5-m eth oxy-1,2,3,4-tetr ah ydr on aph th alen -
-yl)-n -p r op yl]p ip er a zin e (13). Compound 8c was reacted
(
21
1
6
was prepared from 9b hydrochloride
as described
1
for compound 15:
1
H NMR (CDCl ) 1.48-1.88 [mm, 12H,
3
1
CdNCH CH CH and CH(CH CH ) ], 2.17 [t, 2H, J ) 6.6 Hz,
2
2
2
2
2 2
with 1-benzylpiperazine in toluene to give 13 with 86% yield:
NdCCH ], 2.27-2.46 [mm, 6H, CH N(CH ) ], 2.63-2.71 (mm,
2
2
2 2
1
H NMR (CDCl
.73 (mm, 13H, piperazine, CH
s, 2H, NCH Ph), 3.81 (s, 3H, OCH
aromatic); GC/MS m/z 380 (M + 2, 4), 379 (M + 1, 28), 378
3
) 1.46-1.81 [mm, 6H, CH(CH
CH CH N and benzylic), 3.50
), 6.61-7.35 (mm, 8H,
2
CH
2
)
2
], 2.34-
3H, benzylic), 3.29 [t, 4H, J ) 5.0 Hz, (CH ) NC], 3.48 (t, 2H,
2
2
2
(
2
2
2
J ) 5.7 Hz, CdNCH ), 3.75 (s, 3H, OCH ), 6.62-6.97 (mm,
2
3
+
+
2
3
3H, aromatic); GC/MS m/z 371 (M
+ 2, 1), 370 (M + 1, 8),
+
+
+
369 (M , 28), 271 (25), 258 (21), 124 (35), 111 (100).
+
(
M , 98), 189 (100), 161 (19), 134 (21), 91 (98).
-Cycloh exyl-4-[3-(5-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)-n -p r op yl]p ip er a zin e (14). 14 was prepared
from 8c and 1-cyclohexylpiperazine and eluted with CHCl
4
-[4-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-n -
1
bu tyl]-1-[2-(3,4,5,6-tetr a h yd r op yr id yl)]p ip er a zin e (17). 17
was prepared from 4-(4-chloro-n-butyl)-8-methoxy-1,2-dihy-
dronaphthalene and 1-(2-pyridyl)piperazine to give 1,2-dihy-
dronaphthalene intermediate, which was hydrogenated as
3
1
(
3
70% yield): H NMR (CDCl ) 1.04-1.34 (mm, 6H, cyclohexyl),
1
2
.51-2.15 [mm, 12H, cyclohexyl NCH(CH
2
)
2
and CH(CH
CH CH
2
CH
N and
2
)
2
],
1
hydrochloride salt to compound 17, as reported for 15: H NMR
.19-2.73 (mm, 14H, piperazine, NCH, CH
2
2
2
(
CDCl
.18 [t, 2H, J ) 6.6 Hz, NdCCH
CH N(CH ], 2.40 [br t, 4H, J ) 5.0 Hz, CH
.74 (mm, 3H, benzylic), 3.31 [t, 4H, J ) 5.0 Hz, (CH
.48 (t, 2H, J ) 5.7 Hz, CdNCH ), 3.78 (s, 3H, OCH ), 6.61-
.10 (mm, 3H, aromatic); GC/MS m/z 385 (M + 2, 1), 384 (M
3
) 1.23-1.85 [mm, 14H, CH(CH
], 2.32 [t, 2H, J ) 7.4 Hz,
N(CH ], 2.61-
NC],
2 3 2 2 2
) CH N, endo CH CH ],
benzylic), 3.78 (s, 3H, OCH ), 6.61-7.24 (mm, 3H, aromatic);
3
2
2
+
+
+
GC/MS m/z 372 (M + 2, 2), 371 (M + 1, 12), 370 (M , 46),
2
2
)
2
2
2 2
)
1
81 (100), 125 (22), 112 (27).
2
3
7
2 2
)
N-[3-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-n -
p r op yl]-N′-p h en yleth ylen ed ia m in e (20). 20 was prepared
from 8c and N-phenylethylenediamine (70% yield): H NMR
2
3
+
+
1
+
+
1, 11), 383 (M , 40), 161 (10), 124 (40), 111 (100).
-[3-(7-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-n -
p r op yl]p ip er a zin e (18). The N-acetyl derivative 10b (1.0
g, 3.0 mmol) was refluxed in 2 N HCl (45 mL) for 2 h. After
cooling, the mixture was made alkaline with sodim carbonate
Cl . The organic layers
2 2
were dried (Na SO ), and the solvent was evaporated to
produce 0.80 g (2.8 mmol, 93% overall yield) of compound 18
as a colorless oil. Hydrochloride salt was prepared as de-
(
CDCl
exchanged], 2.50-2.80 (mm, 5H, benzylic and CHCH
NH), 2.84-2.88 (mm, 2H, NHCH CH NHPh), 3.20 (mm, 2H,
CH CH NHPh), 3.79 (s, 3H, OCH ), 6.60-7.19 (mm, 8H,
aromatic); GC/MS m/z 340 (M + 2, 1), 339 (M + 1, 5), 338
3
) 1.45-1.87 [mm, 10H, CH(CH
2
CH
2
)
2
and 2 NH, D
2
O
2
1
2
CH CH -
2
2
2
2
2
3
+
+
and extracted three times with CH
+
(
M , 18), 232 (61), 201 (58), 159 (21), 107 (100).
2
4
3
-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-N-(3-
p h en yl-n -p r op yl)-n -p r op yla m in e (21). Title compound was
prepared from 8c and 3-phenyl-n-propylamine in the molar
1
scribed below in the general procedure: H NMR (200 MHz,
ratio 1:3, respectively, eluting with CH
2
Cl
) 1.41-1.86 [mm, 11H, CH(CH
Ph, and NH, D O exchanged], 2.58-2.74 (mm, 9H,
benzylic and CH NHCH ), 3.79 (s, 3H, OCH ), 6.62-7.30 (mm,
2
/CH
3
OH, 9:1 (88%
CDCl
3
) 1.50-1.84 [mm, 8H, CH(CH
2
CH
N(CH )
2
)
2
], 1.95 (br s, 1H, D
], 2.63-2.73 (mm,
NH], 3.76 (s, 3H,
2
O
1
yield): H NMR (CDCl
CH CH CH
3
2
CH
2 2
) ,
exchanged, NH), 2.29 [mm, 6H, CH
3
2
2 2
2
2
2
2
H, benzylic), 2.89 [t, 4H, J ) 4.9 Hz, (CH
OCH ), 6.62-6.98 (mm, 3H, aromatic); GC/MS m/z 290 (M
, 1), 289 (M + 1, 6), 288 (M , 29), 246 (17), 99 (100).
-[3-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-n -
p r op yl]p ip er a zin e (19). Compound 19 was prepared from
0c (1.0 g, 3.0 mmol) as described for 18: pale yellow oil (0.70
2 2
)
2
2
3
+
3
+
+
+
8
3
4
H, aromatic); GC/MS m/z 339 (M + 2, 1), 338 (M + 1, 9),
37 (M , 37), 232 (18), 201 (22), 161 (21), 148 (33), 118 (49),
4 (100).
3
+
+
2
+
1
-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-N-(2-
1
p h en yleth yl)-n -p r op yla m in e (22). 22 was prepared from
1
g, 2.4 mmol, 81% overall yield): H NMR (200 MHz, CDCl
.51-1.81 [mm, 8H, CH(CH CH ], 1.93 (br s, 1H, D
exchanged, NH), 2.29 [mm, 6H, CH N(CH ], 2.59-2.74 (mm,
NH], 3.79 (s, 3H,
3
)
8
9
c and 2-phenylethylamine was eluted with CH
2
Cl
) 1.45-1.82 [mm, 9H, CH-
O exchanged], 2.49-2.89 (mm, 9H,
), 3.78 (s, 3H, OCH ), 6.61-7.31 (mm,
H, aromatic); GC/MS m/z 324 (M+ + 1, 2), 323 (M , 7), 233
17), 232 (100), 159 (21), 147 (18).
-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-N-[2-
1,2,3,4-t e t r a h y d r o n a p h t h a le n -1-y l)e t h y l]-n -p r o p y -
2 3
/CH OH,
1
2
2
)
2
2
O
1
:1 (65% yield): H NMR (CDCl
and NH, D
benzylic and CH NHCH
3
2
2 2
)
(
CH CH
2
)
2
2
2
3
2 2
H, benzylic), 2.89 [t, 4H, J ) 5.5 Hz, (CH )
2
2
3
+
OCH ), 6.61-7.12 (mm, 3H, aromatic); GC/MS m/z 290 (M +
3
+
8
(
+
+
2
, 1), 289 (M + 1, 7), 288 (M , 33), 246 (16), 99 (100), 86 (22).
Hyd r och lor id e Sa lts. Gen er a l P r oced u r e. The hydro-
3
chloride salts were prepared by adding an HCl ethereal
solution to a CH Cl solution of amine followed by recrystal-
lization from CH OH/Et O, unless otherwise reported. They
were obtained as white to sand yellow crystals or crystalline
powders; their crystallization formulas and melting points are
reported in Tables 1 and 2.
P h a r m a cologica l Meth od s. Procedures involving use of
small laboratory rodents and their care were conducted in
conformity with institutional guidelines that are in compliance
with National laws and policies (EEC Council Directive 86/
(
2
2
la m in e (23). Compound 8c was refluxed in benzene with 2-(5-
methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)ethylamine to give
3 which was chromatographed with CHCl
eluent (40% yield): H NMR (CDCl
CH CH , CH CHCH CH , and NH, D
.86 (mm, 10H, benzylic and CH NHCH
3
2
2
3
/Et
2
O, 1:1, as
1
3
) 1.48-1.90 [mm, 15H, CH-
(
2
2
)
2
2
2
2
2
O exchanged], 2.52-
), 3.78 (s, 3H, OCH ),
2
6
3
1
2
2
3
+
.62-7.17 (mm, 7H, aromatic); GC/MS m/z 379 (M + 2, 4),
+
+
78 (M + 1, 29), 377 (M , 100), 232 (29), 201 (27), 158 (33),
30 (25).
6
09 and Italian Government act 116/J anuary 27, 1992).
σ Bin d in g Site Assa ys: [ H]DTG Bin d in g. The method
4
-[3-(1,2,3,4-Tet r a h yd r on a p h t h a len -1-yl)-n -p r op yl]-1-
2-(3,4,5,6-tetr a h yd r op yr id yl)]p ip er a zin e (15). The hy-
drochloride salt of 1-(2-pyridyl)piperazine derivative 9a (2.0
mmol) was dissolved in C OH/CH OH, 1:1 (20 mL), and
3
[
adopted was originally described by Weber et al.29 In brief,
male Guinea pigs (Charles River, Italy) were sacrificed by
cervical dislocation, the brains were rapidly removed, and fresh
cerebral cortices were dissected and homogenized in 10
volumes (wet wt/vol) of 0.32 M sucrose with a Brinkmann
Polytron (setting 5 for 15 s). The homogenate was centrifuged
at 900g at 4 °C; the pellet was discarded, and the supernatant
was centrifuged at 48000g for 20 min at 4 °C. The resulting
pellet was resuspended in 10 volumes (based on the original
2
H
5
3
hydrogenated in the presence of a catalytic amount of 10%
palladium on activated carbon. At the end of the absorption
of hydrogen (24-36 h at normal pressure and room temper-
ature), the mixture was filtered on Celite and concentrated
under reduced pressure. The residue was taken up with a 1%
sodium carbonate solution (20 mL) and extracted twice with
3
CHCl . The solvent was evaporated to obtain the product 15

New σ and 5-HT1A Receptor Ligands
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 181
3
weight) of Tris‚HCl buffer (50 mM, pH 7.4) and incubated at
10 mg of tissue suspension (0.8 mL), 20 nM [ H]5-HT (0.1 mL,
-
1
-10
-5
3
4
7 °C for 30 min. The suspension was then centrifuged at
27 Ci mmol , NEN), and various concentrations (10 -10
8000g for 20 min at 4 °C. The pellet was either used for the
M) of the tested compound (0.1 mL). The tubes were incubated
for 15 min at 37 °C, and the incubations were terminated by
vacuum filtration through Whatman GF/B filters. The filters
were washed three times with 4 mL of ice-cold 50 mM Tris‚-
HCl buffer, pH 7.4, and the radioactivity bound to the filters
was measured by liquid scintillation spectrometry. 5-HT1A
assay or cryopreserved at -80 °C until assayed. The final
pellet was resuspended in Tris‚HCl buffer (50 mM, pH 7.4).
-
10
For displacement experiments, various concentrations (10
-
-
5
1
0
M) of the tested compound and 0.9 nM of tritiated DTG
were used. The tubes were incubated for 90 min at room
temperature, and the incubations were terminated by vacuum
filtration through Whatman GF/B filters. The filters were
washed three times with 5 mL of ice-cold Tris‚HCl buffer, and
the radioactivity bound to the filters was measured by liquid
specific binding was defined as the difference between binding
in the absence and binding in the presence of 10-5 M 8-hy-
droxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and using
-5
1
0
M ketanserin to saturate 5-HT
2
binding sites.
3
scintillation spectrometry. Specific [ H]DTG binding was
5
-HT Bin d in g. The radioligand assay was conducted
2
defined as the difference between binding in the absence and
32
essentially as reported elsewhere (Mir et al. ). Cerebral cortex
from male Sprague-Dawley rats (180-220 g) was homog-
enized in 50 volumes of ice-cold Tris‚HCl buffer (50 mM, pH
binding in the presence of cold DTG (1 µM).
3
[
H]-(+)-P en ta zocin e Bin d in g. The experiments were
30
performed following the method described by Cagnotto et al.
7
.4 at 22 °C) with a Brinkmann Polytron (setting 5 for 15 s),
with minor modifications as briefly described. Male Sprague-
Dawley rats (Charles River, Italy) were sacrificed by decapita-
tion, the brains were rapidly removed, and the whole brain
minus the cerebellum and ponsmedulla oblongata was homog-
enized in 50 volumes (wet wt/vol) of 50 mM Tris‚HCl buffer,
pH 7.8, with a Brinkmann Polytron (setting 5 for 3 × 15 s).
The omogenate was centrifuged at 48000g for 10 min at 4 °C.
The pellets were washed four times by resuspension and
centrifugation. The final pellets were either resuspended in
the incubation buffer or stored at -80 °C until assayed. The
tubes were incubated for 120 min at 25 °C, and the incubations
were terminated by vacuum filtration through Whatman GF/B
filters presoaked in 0.5% polyethylenimine. The filters were
washed three times with 5 mL of ice-cold Tris‚HCl buffer, and
the radioactivity bound to the filters was measured by liquid
and the homogenate was centrifuged at 48000g for 10 min.
The supernatant was discarded, and the pellet was resus-
pended and preincubated for 10 min at 37 °C. The pellet was
washed twice and resuspended in 100 volumes of Tris‚HCl
buffer as described above. To each tube were added the
following: 0.1 mL of the drug dilution (0.1 mL of water if no
3
competing drug was added), 0.1 mL of [ H]ketanserin in Tris‚-
HCl buffer to achieve a final assay concentration of 0.35 nM,
and 0.8 mL of resuspended membranes. The tubes were
incubated for 15 min at 37 °C, and the incubations were
terminated by vacuum filtration through Whatman GF/B
filters. The filters were washed three times with 5 mL of ice-
.
cold Tris HCl buffer, and the radioactivity bound to the filters
was measured by liquid scintillation spectrometry. Specific
3
3
[ H]ketanserin binding was defined as the difference between
scintillation spectrometry. Specific [ H]-(+)-pentazocine bind-
binding in the absence and binding in the presence of 1 µM
cold ketanserin.
ing was defined as the difference between binding in the
absence and binding in the presence of 10 µM haloperidol.
Although this compound is not specific, it is a potent displacer,
the choice was dictated by the difficulties in obtaining cold
pentazocine, due to the restrictions in Italy on laboratory use
of substances of potential abuse, under narcotics bureau
regulations.
D-2 Dop a m in er gic Bin d in g Assa y. The binding assay
for D-2 dopaminergic receptors was essentially as described
3
3
by Briley and Langer and successively modified by Lucchi
et al.34 Corpora striata of male Sprague-Dawley rats were
.
homogenized in 100 volumes of Tris HCl buffer (50 mM, pH
P CP Recep tor Bin d in g Assa y. The binding was per-
7.4) with a Brinkmann Polytron (setting 5 for 15 s); the
homogenate was then centrifuged at 48000g for 10 min. The
supernatant was discarded, and the pellet was washed once.
The final pellet was resuspended in 250 mM NaCl, 5 mM KCl,
3
1
formed as described by Zukin and Zukin with minor modi-
fications. Male Sprague-Dawley rats (Charles River, Italy)
were sacrificed by decapitation, the brains were rapidly
removed, and the hippocampus was dissected and frozen on
dry ice. The hippocampus was then homogenized in 25
volumes (wet wt/vol) of 50 mM Tris‚HCl buffer, pH 7.7, with
a Brinkmann Polytron (setting 5 for 3 × 15 s). The homoge-
nate was centrifuged at 48000g for 10 min at 4 °C. The pellet
was washed twice by resuspension and centrifugation. The
final pellet was either resuspended in the incubation buffer
or stored at -80 °C until assayed. For displacement experi-
2 2
2 mM CaCl , 1 mM MgCl , and 0.1% pargyline. Each assay
3
tube contained 0.1 mL of drug dilution, 0.1 mL of [ H]-
spiroperidol to achieve a final concentration of 0.25 nM, and
0.7 mL of resuspended membranes. The tubes were incubated
for 15 min at 37 °C, and the incubations were terminated by
vacuum filtration through Whatman GF/B filters. The filters
were washed three times with 4 mL of ice-cold Tris‚HCl buffer,
and the radioactivity bound to the filters was measured by
-
10
-5
3
ments, various concentrations (10 -10 M) of the tested
liquid scintillation spectrometry. Specific [ H]spiroperidol
3
compound and 10.0 nM of [ H]phencyclidine were used. The
binding was defined as the difference between binding in the
tubes were incubated for 20 min at 37 °C, and the incubations
were terminated by addition of 6 mL of ice-cold Tris‚HCl buffer
and immediate vacuum filtration through Whatman GF/B
filters presoaked in 0.5% polyethylenimine. The filters were
washed twice with 6 mL of Tris‚HCl buffer, and the radio-
activity bound to the filters was measured by liquid scintilla-
absence and binding in the presence of butaclamol (1 µM).
Ack n ow led gm en t. The financial support from CNR
is gratefully acknowledged.
3
tion spectrometry. Specific [ H]phencyclidine binding was
defined as the difference between binding in the absence and
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(
1) Howard, H. R.; Seeger, T. F. Novel Antipsychotics. Annu. Rep.
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Hippocampi from male Sprague-Dawley rats were homog-
enized in 25 volumes (based on the wet weight) of ice-cold
Tris‚HCl buffer (50 mM, pH 7.6). The homogenate was
centrifuged at 48000g for 15 min and then washed with the
same buffer. The pellet was resuspended in 25 volumes of the
same buffer and incubated at 37 °C for 15 min. After the
incubation the homogenate was centrifuged at 48000g for 15
min. The final pellet was frozen and stored at -80 °C until
assayed. For the binding assay each tube received, to achieve
a final volume of 1 mL, 50 mM Tris‚HCl containing 4 mM
(
3) Gilligan, P. J .; Tam, S. W. Sigma receptor ligands: potential
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1
994, 7, 13-18.
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(
5) Largent, B. L.; Gundlach, A. L.; Snyder, S. H. Pharmacological
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3
receptor binding sites in brain with (+)-[ H]SKF 10,047, (+)-
3
3
[
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82 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
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(
(
(
(
6) Quirion, R.; Chicheportiche, R.; Contreras, P. C.; J ohnson, K.
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Characterization of the binding of [ H]-(+)-pentazocine to σ
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1
04.
3
(
(
(
22) Formerly unpublished results: IC50 ) 652 nM on [ H]DTG for σ
4
3
1
receptor, IC50 > 10 nM on [ H]prazosin for R receptor.
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3
-[5-(5,6,7,8-Tetrahydro)-chinolyl]-alanin. (Bicyclic R-amino ac-
ids. IV: Synthesis of 3-(1-tetralinyl)- and 3-(5,6,7,8-tetrahydro-
-quinolinyl)alanine.) Arch. Pharm. 1983, 316, 297-302.
(
(
(
10) Booth, R. G.; Wyrick, S. D. A novel brain receptor recognized by
phenylaminotetralins may represent sigma (σ ) receptor
a
3
5
subtype. Med. Chem. Res. 1994, 4, 225-237.
(
25) Perrone, R.; Berardi, F.; Leopoldo, M.; Tortorella, V.; Lograno,
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