trans-2-Aryl-N,N-dipropylcyclopropylamines: Synthesis and interactions with 5-HT(1A) receptors

Article abstract of DOI:10.1021/jm9507136

Twelve N,N-dipropyl-substituted derivatives of trans-2- arylcyclopropylamine have been prepared and assayed for their ability to displace [³H]-8-OH-DPAT from rat brain 5-HT(1A) receptors. The new derivatives include phenyl (7a), bromo- (7b) and fluorophenyl (7c-e), 2- methoxy-5-fluorophenyl (7h), and 2-hydroxy-5-fluorophenyl (71) as well as trifluoromethylphenyl (7f) and 2,3-dichlorophenyl (7g) analogues. In the present series of compounds, electron-withdrawing substituents in the phenyl ring appear to decrease the affinity for 5-HT(1A) receptors. In contrast, electron-rich aryl groups, such as 2- or 3-thienyl (7j and 7k, respectively), provide compounds with high affinity. The additional bulk produced by the aromatic moiety in the 2-benzothienyl derivative 7i appears to be detrimental to 5-HT(1A) receptor affinity. The racemic mixtures of the interesting 7j and 7l were resolved into the enantiomers; 7j and 7l exhibited a high enantiomeric 5-HT(1A) receptor affinity ratio (75-fold and 100-fold, respectively). The enantiomers of 7j and 7l were evaluated in vivo by use of biochemical and behavioral tests in rats. Compound (1R,2R)-7j behaved as a partial agonist whereas (1R,2S)-7l appeared as an efficacious 5-HT(1A) receptor agonist, stimulating both autoreceptors and postsynaptic receptors.

Full text of DOI:10.1021/jm9507136

J . Med. Chem. 1996, 39, 1485-1493
1485
tr a n s-2-Ar yl-N,N-d ip r op ylcyclop r op yla m in es: Syn th esis a n d In ter a ction s w ith
5-HT1A Recep tor s
J erk Vallga˚rda,†, Ulf Appelberg,† Lars-Erik Arvidsson,†,| Stephan Hjorth,‡ Bjo¨rn E. Svensson,§,# and
Uli Hacksell*,†
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Box 574, Uppsala University,
S-751 23 Uppsala, Sweden, Department of Pharmacology, University of Go¨teborg, Medicinaregatan 7,
S-413 90 Go¨teborg, Sweden, and Preclinical R & D, Astra Arcus AB, S-151 85 So¨derta¨lje, Sweden
Received September 27, 1995X
Twelve N,N-dipropyl-substituted derivatives of trans-2-arylcyclopropylamine have been pre-
pared and assayed for their ability to displace [3H]-8-OH-DPAT from rat brain 5-HT1A receptors.
The new derivatives include phenyl (7a ), bromo- (7b) and fluorophenyl (7c-e), 2-methoxy-5-
fluorophenyl (7h ), and 2-hydroxy-5-fluorophenyl (7l) as well as trifluoromethylphenyl (7f) and
2,3-dichlorophenyl (7g) analogues. In the present series of compounds, electron-withdrawing
substituents in the phenyl ring appear to decrease the affinity for 5-HT1A receptors. In contrast,
electron-rich aryl groups, such as 2- or 3-thienyl (7j and 7k , respectively), provide compounds
with high affinity. The additional bulk produced by the aromatic moiety in the 2-benzothienyl
derivative 7i appears to be detrimental to 5-HT1A receptor affinity. The racemic mixtures of
the interesting 7j and 7l were resolved into the enantiomers; 7j and 7l exhibited a high
enantiomeric 5-HT1A receptor affinity ratio (75-fold and 100-fold, respectively). The enantiomers
of 7j and 7l were evaluated in vivo by use of biochemical and behavioral tests in rats. Compound
(1R,2R)-7j behaved as a partial agonist whereas (1R,2S)-7l appeared as an efficacious 5-HT1A
receptor agonist, stimulating both autoreceptors and postsynaptic receptors.
In tr od u ction
focused on variations of the phenolic substitution pat-
tern and of the alkyl groups on the amino group. In
the present study we have prepared a series of 12
racemic derivatives (7a -l) in which the N,N-dipropyl-
cyclopropylamine moiety has been kept constant and in
which the aromatic part has been varied. We have also
prepared the enantiomers of the 5-fluoro-2-methoxy-
phenyl (7h ), 5-fluoro-2-hydroxyphenyl (7l), and 2-thienyl
(7j) derivatives. The compounds were studied for their
ability to displace [3H]-8-OH-DPAT from 5-HT1A recep-
tors. In addition, four selected derivatives were evalu-
ated in vivo by use of biochemical and behavioral studies
in rats.
The putative involvement of serotonergic 5-HT1A
receptors in anxiety and depression has generated a
considerable interest in the medicinal chemistry of
selective 5-HT1A receptor agonists and antagonists.1 A
large number of 2-aminotetralin and arylpiperazine
derivatives display high affinity and selectivity for the
5-HT1A receptors.2 The 2-arylcyclopropylamine deriva-
tives constitute another structural class of 5-HT1A
ligands that has been much less investigated. However,
trans-cyclopropylamines 1 and 2 have been identified
as potent and selective 5-HT1A receptor agonists.3 In
contrast to the prototypal 5-HT1A receptor agonist
8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 3),4
which exhibits a low stereoselectivity in its interactions
with 5-HT1A receptors, phenylcyclopropylamine deriva-
tive 1 appears to be highly stereoselective; the affinity
and potency of (1R,2S)-1 is much higher than that of
the antipode.3,5
Ch em istr y
The synthesis of the test compounds is described in
Scheme 1; trans arylated methyl acrylates 4 were
prepared from the corresponding aryl iodides by a
palladium-catalyzed coupling with methyl acrylate un-
der phase transfer conditions.6
4-Fluoro-2-iodoanisole is not commercially available.
Attempts to prepare the compound regioselectively
failed; we never achieved a regiospecific formation of
an anion in the 2-position of 4-fluoroanisole and the 2-
and 3-halogenated regioisomers were nonseparable. The
best regioselectivity was accomplished at room temper-
ature, but the yield was unacceptably low at this
temperature. Consequently, an alternative synthetic
route was chosen:7a 4-Fluoroanisole was chloromethy-
lated in the 2-position with dimethoxymethane in a
hydrochloric acid-sulfuric acid mixture, and the result-
ing intermediate was treated with hexamethylenetet-
raamine and acetic acid to form 4-fluoro-2-methoxyben-
zaldehyde which was converted into the corresponding
trans-phenylpropenoate (4h ) by a Knoevenagel conden-
sation with malonic acid followed by esterification with
methanol (Scheme 2).
Our previous study of structure-activity relationships
(SAR) of trans-2-arylcyclopropylamine derivatives3 was
† Uppsala Biomedical Center.
‡ University of Go¨teborg.
§ Astra Arcus AB.
Present address: Pharmacia AB, Pharmaceuticals, S-751 82
Uppsala, Sweden.
| Present address: Pharmacia Bioprocess Technology, Research and
Development, S-751 82 Uppsala, Sweden.
#
Present address: Preclinical R & D, Astra Pain Control AB, S-151
85 So¨derta¨lje, Sweden.
X Abstract published in Advance ACS Abstracts, March 1, 1996.
0022-2623/96/1839-1485$12.00/0 © 1996 American Chemical Society

1486 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7
Valga˚rda et al.
Sch em e 1a
Sch em e 3a
a
Reagents: (a) (i) NaOH, MeOH, H2O, (ii) C2O2Cl2, (iii) L-(+)-
camphorsultam sodium salt; (b) CH2N2, Pd(OAc)2; (c) (i) Ti(i-PrO)4,
BzOH, (ii) 2 M NaOH, MeOH, THF (method IV).
a
Reagents: (a) methyl acrylate, Pd(OAc)2, NBu4Cl, K2CO3,
DMF (method I); (b) (i) CH2N2, Pd(OAc)2, (ii) NaOH, H2O, MeOH
(method III); (c) DPPA, NEt3, t-BuOH (method V); (d) (i) NEt3,
EtOCOCl, acetone, (ii) NaN3, (iii) t-BuOH, (iv) HCl (method VI);
(e) (i) NEt3, EtOCOCl, acetone, (ii) NaN3, (iii) TMS(CH2)2OH, (iv)
NBu4F, THF (method VII); (f) PrI, K2CO3, acetonitrile (method
VIII).
from the hydrolysis (tetrabutylammonium fluoride or
iodotrimethylsilane11) of the carbamate function in the
2-furylcyclopropyl derivative.
The trans stereochemistry of the primary amines (6)
was confirmed by analysis of vicinal proton-proton
Sch em e 2a
coupling constants of the cyclopropyl moiety (J H1-H2
∼
3.5-3.8 Hz). Compounds 6 were N,N-dipropylated by
treatment with 1-iodopropane to afford the correspond-
ing tertiary amines (7). Methoxy derivative 7h was
O-demethylated by treatment with hydrobromic acid to
form the phenol 7l.
In order to obtain (1S,2R)-7l and (1S,2S)-7j, we
prepared the (+)-enoyl sultams from L-(+)-camphorsul-
tam and the methyl acrylate derivatives 4h and 4j (see
Scheme 3; the D-(-)-camphorsultam was used in the
preparation of the antipodes). The enoyl sultams were
cyclopropanated, and the products were recrystallized
to provide the corresponding cyclopropanoyl derivatives
of high diastereomeric purities.7 The camphorsultam
moiety of the diastereoisomers was removed by a two-
step procedure involving (a) treatment with titanium-
(IV) isopropoxide in benzyl alcohol and (b) base-
promoted hydrolysis of the resulting benzyl ester, thus
providing the enantiomers of 5h and 5j. Test com-
pounds were prepared from the enantiomers of 5h and
5j according to methods described above.
a
Reagents: (a) (i) n-BuLi, THF, -78 f -25 °C, (ii) I2, -78 °C
f room temperature; (b) (i) concentrated HCl/concentrated H2SO4,
70 °C, (ii) hexamethylenetetramine, 50% aqueous HOAc, reflux;
(c) (i) malonic acid, piperidine/pyridine, room temperature f 60
°C, (ii) ∆ (100 °C), (iii) catalytic H2SO4, MeOH, reflux.
The arylated methyl acrylate derivatives were cyclo-
propanated with diazomethane in the presence of 0.005
equiv of palladium(II) acetate.8 Higher concentrations
of the catalyst often led to precipitation of palladium-
(0) with accompanying termination of the reaction.
Alkaline hydrolysis gave the desired trans-arylcyclo-
propanecarboxylic acids 5 (Scheme 1). These acids were
transformed to the corresponding primary amines by
Curtius rearrangements; the one-pot procedure with
diphenyl phosphorazidate9 worked well in many cases
but occasionally produced a complex reaction mixture.
Therefore, an alternative method was used for most of
the compounds that involved preparation of a mixed
anhydride which was treated with sodium azide. The
resulting acyl azides were transformed into tert-butyl
carbamates via the the corresponding isocyanates.
These carbamates were hydrolyzed with 1 M hydrochlo-
ric acid. However, when the aryl moiety was acid
sensitive we prepared the 2-(trimethylsilyl)ethyl car-
bamate, which was hydrolyzed with tetrabutylammo-
nium fluoride.10 Due to decomposition of the aryl
moiety, we were not able to isolate the desired product
Physical data of the new compounds are presented
in Tables 1 and 2.
P h a r m a cology
Affin ity for 5-HT1A Recep tor s in Vitr o. The af-
finities of the N,N-dipropylcyclopropylamine derivatives
for rat hippocampal and cortical 5-HT1A receptors were
determined in competition studies with [3H]-8-OH-
DPAT. In addition, the structurally related and previ-
ously reported3 enantiomers of 1, 2, and 10 were
evaluated in the same assay for comparison. The Ki
values are reported in Table 3.
In Vivo Bioch em istr y. The rationale for the in vivo
biochemical experimental protocol is based on the well-
established phenomenon of (auto)receptor-mediated
feedback inhibition of presynaptic monoaminergic
neurones.12-15 Thus, the synthesis rate of the cat-
echolamines dopamine (DA) and norepinephrine (NE)
is inhibited by agonists via an action at DA receptors
and R-adrenoceptors, respectively. Similarly, the syn-
thesis rate of serotonin (5-HT) is inhibited by 5-HT

trans-2-Aryl-N,N-dipropylcyclopropylamines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7 1487
Ta ble 1. Physical Data of Some Substituted Methyl Propenoates
COOCH3
Ar
compd
Ar
2-BrPh
2-FPh
3-FPh
prepna method
yield, %
mp, °C
oilb
bp, °C/mmHg
formula
4b
4c
4d
4e
4f
4g
4h
4i
I
I
I
I
I
I
II
I
I
80
84
73
92
78
88
94
75
96
50
C10H9BrO2
C10H9FO2
122-123/9.5c,d
68-70/0.05c,d
114-116/4.5c,d
66-68/0.1c
C10H9FO2‚1/8H2O
C10H9FO2
4-FPh
2-CF3Ph
2,3-(Cl)2Ph
5-F,2-OCH3Ph
benzothienyl
2-thienyl
3-thienyl
C11H9F3O2
C10H8Cl2O2
C11H11FO3
C12H10O2S
69-71
43-44
124-125.5e
46-47f
4j
4k
C8H8O2S
I
70-72/0.08c,g
C8H8O2S‚1/8H2O
a
b
d
g
See Experimental Section. Reference 30. c Purified by distillation. Reference 31. e Reference 32. f Reference 33. Reference 34.
receptor agonists. The accumulation of 3,4-dihydroxy-
phenylalanine (DOPA), following decarboxylase inhibi-
tion by means of 3-hydroxybenzylhydrazine (NSD1015;
100 mg/kg sc), was used as an index of the DA synthesis
rate in the DA-rich parts (limbic forebrain, striatum)
and of the NE synthesis rate in the remaining NE-
predominated portions (mainly cortex). The accumula-
tion of 5-hydroxytryptophan (5-HTP) following decar-
boxylase inhibition was taken as an indicator of the
5-HT synthesis rate in all three brain parts (Figure 1).
Reserpine-pretreated rats (5 mg/kg, 18-20 h before)
were used throughout this study. Reserpine depletes
central monoamine stores, thereby facilitating the as-
sessment of direct receptor agonist properties of the test
compounds, both with regard to biochemical and be-
havioral effects.16
tatively similar to that seen after the reference 5-HT1A
receptor agonist 3. In contrast, the effects of (1R,2R)-
7j were at best mild, even at the highest dose tested
(35 µmol/kg sc; Table 4). (1S,2R)-7l failed to induce any
appreciable behavioral change under these conditions.
Discu ssion
The previously prepared (1R,2S)-enantiomers of 2-
and 3-hydroxy derivatives 1 and 2 had 177- and 29-fold
higher 5-HT1A receptor affinity, respectively, than the
(1S,2R)-antipodes (Table 3). This is consistent with
earlier studies of the in vivo 5-HT1A receptor agonist
properties of these derivatives.3 The 2-methoxyphenyl
derivative (1R,2S)-10 was only about 3-fold less potent
than the phenolic analogue (1R,2S)-1. A similar low-
affinity ratio has been reported between the 8-hydroxy
and 8-methoxy derivatives of 2-(dipropylamino)tetralin
(3 and 11, respectively).18 Additional comparisons with
The (1R,2R)-enantiomer of 7j and the (1R,2S)-enan-
tiomer of 7l decreased the cerebral 5-HT synthesis rate
by about 50% from control values at the highest doses
tested (35 µmol/kg sc) (Figure 1). This is similar to the
maximum 5-HT synthesis reduction elicited by (1R,2S)-
1,3 and the reference 5-HT1A receptor agonist 3.4
A
rough graphical approximation of the doses required to
produce a half-maximal suppression of the 5-HT syn-
thesis indicates that (1R,2S)-7lsthe 5-fluorinated de-
rivative of (1R,2S)-1sand the thienyl analogue (1R,2R)-
7j display similar potency (∼1.5-3 µmol/kg), both being
about 5-10 times less potent than (1R,2S)-1 (cf. ref 3).
None of the compounds tested caused any significant
change in rat brain DOPA accumulation (data not
shown). This was true in both DA-rich (limbic forebrain,
striatum) and NA-predominated (cortex) brain areas,
and suggests lack of potent DA and NA R-receptor
stimulatory properties, respectively.
5-HT Syn d r om e a n d Gr oss Beh a vior a l Obser va -
tion s. Stimulation of postsynaptic 5-HT1A receptors by
means of, for example, administration of 3 results in a
clear-cut motor behavioral syndrome, the “5-HT syn-
drome”, in rats. Flattened body posture, forepaw tread-
ing, and hindlimb abduction are the most prominent
features of this syndrome.4c,17 The ability of the test
drugs to elicit putative postsynaptic 5-HT1A receptor
agonist properties was thus assessed by rating the
occurrence and intensity of these behavioral components
in the reserpinized rats (Table 4).16 The gross behavior
of the animals was observed in their home cages.
Immediately after the scoring session the rats were
injected with NSD1015 and subsequently used for
determination of brain 5-HT and catecholamine syn-
thesis rates (cf. above). (1S,2S)-7j and (1R,2S)-1 both
induced a clear-cut 5-HT behavioral syndrome, quali-
the 2-aminotetralin series can be made: In studies of
C8-substituted 2-(dipropylamino)tetralin derivatives it
has been demonstrated that most of the affinity for
5-HT1A receptors is retained when the C8-substituent
is replaced by a hydrogen.18 A similar trend was
observed in the present study since phenyl derivative
7a is about 5-fold less potent than the 2-hydroxyphenyl
analogue (1R,2S)-1 (Table 3). These findings point to
similarities in the SAR of the two series and indicates
that the modes of binding of the 2-aminotetralin and
arylcyclopropylamine derivatives to the 5-HT1A recep-
tors are similar (compare the SAR discussion in refs 19
and 20).
When the affinities of the halogen-substituted deriva-
tives are compared with that of the phenyl derivative
7a , it is apparent that halogen substitution in the
phenyl ring does not affect (2-Br, 7b), decreases (2-F,
3-F, or 4-F; 7c, 7d , or 7e, respectively), or abolishes (2,3-
Cl2; 7g) the affinity for 5-HT1A receptors (Table 3).
Introduction of the strongly electron withdrawing tri-
fluoromethyl group in the C2-position of the phenyl
moiety, affording 7f, also abolished affinity. These data
indicate that the introduction of electron-withdrawing
substituents in the phenyl ring is detrimental for
affinity. In contrast, hydroxyl groups, which enhance

1488 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7
Ta ble 2. Physical Data of Cyclopropyl Compounds
Valga˚rda et al.
Y
Ar
compd
Ar
Y
prepn meth
yield, %
mp, °C
recrystn solventsa
formula
5a
5b
5c
5d
5e
5f
Ph
2-BrPh
2-FPh
3-FPh
4-FPh
2-CF3Ph
2,3-(Cl)2Ph
5-F,2-OCH3Ph
5-F,2-OCH3Phe
5-F,2-OCH3Phf
benzothienyl
2-thienyl
2-thienyli
2-thienylj
3-thienyl
Ph
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
N(n-C3H7)2
IIIb
III
III
III
III
III
III
III
IV
IV
III
III
IV
IV
III
V
VI
V
VI
VI
VI
V
VI
VI
VI
91
75
92
90
94
69
63
89
93
92
84
87
60
78
91
45
45
40
85
68
63
43
58
58
59
82
36
58
49
35
56
75
41
52
63
33
74
75
42
48
41
94
56
80
68
65
52
58
89.5-90.5c
106-107.5
oil
NRd
NR
C10H10O2
C10H9BrO2
C10H9FO2‚1/8H2O
80-81
NR
NR
F
NR
NR
NR
NR
C
C10H9FO2
C10H9FO2
110-112
117-118.5
129.5-130.5
165.5-166.5
125.5-126
125.5-126
165.5-167g
46-48h
C11H9F3O2
C10H8Cl2O2
C11H11FO3
C11H11FO3
C11H11FO3
C12H10O2S
C8H8O2S
C8H8O2S
5g
5h
(1S,2S)-5h
(1R,2R)-5h
5i
5j
(1S,2S)-5j
(1R,2R)-5j
5k
6a
6b
6c
6d
6e
6f
6g
6h
(1S,2R)-6h
(1R,2S)-6h
6i
6j
(1S,2S)-6j
(1R,2R)-6j
6k
7a
7b
7c
7d
7e
7f
7g
7h
NR
oil
oil
73-75
C8H8O2S
C8H8O2S
C9H11N‚HCl
NR
A
A
A
A
m
A
A
B
A
A
A
A
A
A
A
A
A
D
E
D
A
A
A
A
A
A
A
A
A
A
A
A
A
154-156c
172-174
130-133k
181-184k
190-192k,l
177-179
193-195
201.5-203.5
213.5-216
215-218
190g,l
2-BrPh
2-FPh
3-FPh
4-FPh
C9H10BrN‚HCl
C9H10FN‚HCl
C9H10FN‚HCl
C9H10FN‚HCl
C10H10F3N‚HCl
C9H9Cl2N‚HCl‚1/4H2O
C10H12FNO‚HCl
C10H12FNO‚HCl
C10H12FNO‚HCl
C11H11NS‚C2H2O4‚1/4H2O
C7H9NS‚1/2C2O4H2
C7H9NS‚1/2C2O4H2
C7H9NS‚C2O4H2
C7H9NS‚C2O4H2
C15H23N‚HCl
2-CF3Ph
2,3-(Cl)2Ph
5-F,2-OCH3Ph
5-F,2-OCH3Phn
5-F,2-OCH3Pho
benzothienyl
2-thienyl
2-thienylp
2-thienylq
3-thienyl
Ph
VI
VII
VII
VII
VII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
IX
174-175g,l
178-180
207-210l
171-172l
154-155
148.5-150.5
93-94
2-BrPh
2-FPh
3-FPh
4-FPh
C15H22BrN‚HCl
C15H22FN‚HCl
C16H23N‚HCl
148-151
117-119
130-132
141-143
154.5-156
163-165
163.5-165
132-133.5
83-85
C16H23N‚HCl
2-CF3Ph
C16H22F3N‚HCl
C15H21Cl2N‚HCl
C16H24FNO‚HCl
C16H24FNO‚HCl
C16H24FNO‚HCl
C17H23NS‚HCl‚1/4H2O
C13H21NS‚C2O4H2‚1/4H2O
C13H21NS‚HCl‚1/8H2O
C13H21NS‚HCl‚1/4H2O
C13H21NS‚HCl
C15H22FNO‚HCl
C15H22FNO‚HCl
C15H22FNO‚HCl
2,3-(Cl)2Ph
5-F,2-OCH3Ph
5-F,2-OCH3Phr
5-F,2-OCH3Phs
benzothienyl
2-thienyl
2-thienylt
2-thienylu
3-thienyl
5-F,2-OHPh
5-F,2-OHPhv
5-F,2-OHPhw
(1S,2R)-7h
(1R,2S)-7h
7i
7j
(1S,2S)-7j
(1R,2R)-7j
7k
172-175l
170-172l
150-52
167.5-169
169-172
170-174
7l
(1S,2R)-7l
(1R,2S)-7l
IX
IX
a
A ) methanol/ether, B ) ethanol/ether, C ) toluene, D ) ether (after several days at -25 °C), E ) 2-propanol/ether, F ) ether.
Prepared from the commercially available methyl cinnamate. c Reference 35. Not recrystallized due to high initial purity. e [R]22
)
b
d
D
+211 (c ) 1.0, CH2Cl2). f [R]22D ) -212 (c ) 1.0, CH2Cl2). Reference 36. Reference 37. [R]22D ) +328 (c ) 1.0, CH2Cl2). [R]22D ) -326
g
h
i
j
(c ) 1.1, CH2Cl2). Reference 38. Decomposed. Not recrystallized, decomposed on attempt to recrystallize from methanol/ether. [R]22
k
l
m
n
D
)
)
) +42.0 (c ) 1.0, MeOH). o [R]22 ) -41.3 (c ) 1.0, MeOH). [R]22 ) +77.4 (c ) 0.6, MeOH). [R]22 ) -57.0 (c ) 0.9, MeOH), [R]22
p
q
D
D
D
D
-58.8 (c ) 0.5, MeOH). [R]22 ) +8.9 (c ) 1.0, MeOH). [R]22 ) -9.4 (c ) 1.0, MeOH). [R]22 ) +75.2 (c ) 1.0, MeOH). [R]22
r
s
t
u
D
D
D
D
-76.3 (c ) 1.1, MeOH). v [R]22 ) +6.8 (c ) 1.0, MeOH). [R]22 ) -7.8 (c ) 1.0, MeOH).
w
D
D
the electron density of the aromatic ring, appear to be
beneficial for 5-HT1A receptor affinity (cf. above).
Three compounds with electron-rich heteroaromatic
rings, 2-thienyl (7j), 3-thienyl (7k ), and 2-benzothienyl
(7i), were synthesized and tested as potential bioiso-
steres of the potent phenolic derivatives 1 and 2 (Table
3). The 2-thienyl derivative 7j proved to be a potent
5-HT1A receptor ligand, the affinity being 2-3-fold less
than that of the phenolic analogues 1 and 2. The
affinity of the 3-thienyl analogue 7k was slightly lower.
It thus appears that the 2- and 3-thienyl rings constitute
good isosteric replacements for the 2- and 3-hydroxy-
phenyl moieties in 1 and 2. The 2-benzothienyl deriva-
tive 7i was inactive, most likely due to the steric bulk
of the fused phenyl moiety.
Because of the high affinity of racemic 7j, we synthe-
sized and tested the enantiomers. As might have been
predicted on the basis of previously observed stereose-
lectivities in the phenylcyclopropylamine series,3,5 7j
exhibited a large enantiomeric affinity ratio, the affinity
of the (1R,2R)-enantiomer being 75-fold higher than that
of the antipode. In the ex vivo biochemical experiments,
(1R,2R)-7j behaved as a full 5-HT1A receptor agonist but
of slightly lower potency than (1R,2S)-1. In contrast,
the antipode, (1S,2S)-7j, was unable to reduce the
5-HTP levels even at the highest dose level (35 µmol/
kg) (Figure 1). It is noteworthy that neither enantiomer
of 7j induced a clear-cut 5-HT behavioral syndrome
(Table 4) in the reserpinized rats. Thus, the high
5-HT1A receptor affinity of 7j (Table 2) was accompanied

trans-2-Aryl-N,N-dipropylcyclopropylamines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7 1489
J NM-EX270 spectrometer at 270 MHz, and 13C NMR spectra
were recorded on a J EOL FX 90Q spectrometer at 22.5 MHz,
except where noted. NMR spectra were referenced to internal
tetramethylsilane. GLC analysis was performed on a Shi-
madzu GC14A equipped with a FID detector and a HP-1
column (50 m × 0.32 mm). Mass spectral analysis was
performed on a Hewlett-Packard mass spectrometer HP 5971A
MSD connected to a gas chromatograph HP GC 5890 Series
2, equipped with a HP-1 column (25 m × 0.2 mm). Optical
rotations were obtained on a Perkin-Elmer 241 polarimeter.
The elemental analyses (C, H, and N), which were performed
by Micro Kemi AB, Uppsala, Sweden, were within 0.4% of the
theoretical values. TLC analysis was carried out on aluminum
sheets precoated with silica gel F254 (0.2 mm) or on Al2O3 60
F254 neutral (Typ E), E. Merck, and was visualized with UV
light and/or I2. All reactions except the cyclopropanations were
performed under nitrogen.
Ta ble 3. Affinities for 5-HT1A Receptors Defined by the
Displacement of [3H]-8-OH-DPAT
compd
Ki, nM
range
nH
7a
7b
7c
7d
7e
7f
24
22
59
100
76
(21-28)
(20-23)
(48-77)
(85-130)
(63-95)
0.88
0.87
0.94
0.74
0.83
>1000
>300
140
199
60
7g
7h
(89-280)
(174-224)
(39-87)
0.52
0.90
0.80
(1S,2R)-7h
(1R,2S)-7h
7i
>1000
7j
13
(12-14)
0.94
1.00
0.96
0.93
0.84
0.90
0.88
0.90
0.97
0.70
0.80
0.90
0.75
(1S,2S)-7j
(1R,2R)-7j
7k
820
11
21
99
348
3.2
140
4.9
460
2.6
(710-980)
(10-13)
2-Iod oben zoth iop h en e.23 Benzothiophene (10 g, 75 mmol)
was dissolved in ether (100 mL). The solution was cooled to 0
°C, and butyllithium (1.6 M in hexane, 49 mL, 78 mmol) was
added. After 3.5 h the solution was cooled to -50 °C, iodine
(18.9 g, 75 mmol) was added, and the reaction temperature
was slowly increased to room temperature. Saturated aqueous
NH4Cl (50 mL) and saturated aqueous Na2S2O3 (70 mL) were
added to the mixture. The organic layer was separated,
washed with H2O (2 × 100 mL), dried (MgSO4), filtered, and
concentrated. The crude product was purified by distillation
(bp 153-156 °C/14 mmHg). The resulting oil was dissolved
in hexane. The solution was treated with charcoal, filtered,
and concentrated to afford 8.31 g (43%) of pure 2-iodoben-
zothiophene as an oil: 1H NMR (acetone-d6, 90 MHz) δ 7.96-
7.77 (m, 2 H), 7.71 (s, 1 H), 7.44-7.23 (m, 2 H); 13C NMR
(acetone-d6) δ 145.0, 141.8, 134.9, 125.4, 125.3, 123.2, 122.1,
79.2.
Below are examples of the methods described in Scheme 1:
Met h yl tr a n s-3-(2-Br om op h en yl)p r op en oa t e (4b ).
Meth od I. A mixture of 2-bromoiodobenzene (7.0 g, 24.7
mmol), methyl acrylate (2.8 mL, 31.9 mmol), tetrabutylam-
monium chloride (6.9 g, 24.7 mmol), Pd(OAc)2 (0.11 g, 0.5
mmol), and finely grounded K2CO3 (8.55 g, 62 mmol) in DMF
(26 mL) was stirred at 50 °C for 19 h. Petroleum ether (150
mL) and brine (40 mL) were added, and the mixture was
filtered under suction. The filtrate was collected, and the
aqueous layer was extracted with petroleum ether (3 × 100
mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated. The residue was purified on a silica
column (ether/petroleum ether, 1:4) to afford 4.8 g of pure 4b:
1H NMR (CDCl3, 90 MHz) δ 8.06 (d, J ) 16.0 Hz, 1 H), 7.66-
7.55 (m, 2 H), 7.41-7.10 (m, 2 H), 6.38 (d, J ) 16.0 Hz, 1 H),
3.82 (s, 1 H); 13C NMR (CDCl3) δ 166.7, 143.1, 134.4, 133.4,
131.2, 127.7 (2 C’s), 125.3, 120.6, 51.8.
(19-23)
7l
(78-140)
(184-503)
(2.7-3.6)
(100-230)
(4.6-5.2)
(240-760)
(2.2-3.2)
(160-430)
(16-20)
(1S,2R)-7l
(1R,2S)-7l
(1S,2R)-1
(1R,2S)-1
(1S,2R)-2
(1R,2S)-2
(1S,2R)-10
(1R,2S)-10
230
17
by potent agonist properties in the ex vivo biochemical
model, but low apparent efficacy (if any) in the behav-
ioral test model, reflecting, respectively, the ability to
activate synthesis controlling 5-HT1A autoreceptors and
postsynaptic 5-HT1A receptors mediating the 5-HT
behavioral syndrome in reserpinized rats. These data
are consistent with a characterization of (1R,2R)-7j as
a partial 5-HT1A receptor agonist. Thus, the isosteric
replacement of the hydroxyphenyl moiety of (1S,2R)-1
with a 2-thienyl ring appears to result in a considerable
loss in efficacy, manifested under the present conditions
only at the level of postsynaptic 5-HT1A receptors, likely
due to differences in apparent receptor reserve (cf. ref
21). In contrast, most of the affinity is retained.
Meth yl tr a n s-3-(5-Flu or o-2-m eth oxyph en yl)pr open oate
(4h ). Meth od II. Concentrated H2SO4 (3 mL) was added to
a solution of trans-3-(5-fluoro-2-methoxyphenyl)propenoic acid7a
(6.0 g, 30.6 mmol) in MeOH (150 mL). The solution was
heated to reflux for 5 h. Saturated aqueous Na2CO3 was added
to the resulting solution until neutral pH. The solution was
filtered and concentrated. The residue was partitioned be-
tween ether (100 mL) and H2O (150 mL). The organic layer
was washed with H2O (100 mL), dried (MgSO4), filtered, and
concentrated. The residue was purified on a silica column
eluted with ether/petroleum ether (1:4) to afford 4h as a white
solid.
tr a n s-2-(2-F lu or op h en yl)cyclop r op a n eca r boxylic Acid
(5c). Meth od III. Diazomethane (CAUTION)24 was prepared
as previously described;24 a solution of N-methyl-N-nitroso-4-
toluenesulfonamide (Diazogen, 5.95 g, 27.8 mmol) in ether (60
mL) was slowly added to a heated (70 °C oil bath) mixture of
KOH (4.67 g, 83.3 mmol), ether (10 mL), H2O (50 mL), and
2-(2-ethoxyethoxy)ethanol (50 mL). The resulting ether solu-
tion of diazomethane was continuously distilled into a stirred,
cooled (-10 °C) solution of 4c (0.50 g, 2.8 mmol) and Pd(OAc)2
(3.1 mg, 0.0014 mmol) in CH2Cl2/ether (1:2; 75 mL). The
reaction was quenched by addition of a few milliliters of HOAc
after 1.5 h. The resulting mixture was washed with saturated
aqueous NaHCO3 (2 × 3 mL), dried (MgSO4), filtered, and
Introduction of a C5-fluoro substituent in 2-aminote-
tralin derivative 3, producing 12 (UH-301),22 reduces
mainly efficacy but also affinity. Thus, (R)-12 is a
partial 5-HT1A receptor agonist whereas (R)-3 is a full
agonist, and (S)-12 is a 5-HT1A receptor antagonist
whereas (S)-3 is a partial agonist.5 Similar effects were
not observed when a C5-fluoro substituent was intro-
duced in the cyclopropylamine-derived agonist (1R,2S)-
1; (1R,2S)-7l had about the same affinity as (1R,2S)-1
and displayed clear-cut in vivo biochemical (Figure 1)
as well as behavioral (Table 4) agonist activity. (1S,2R)-
7l, on the other hand, was 100-fold less potent than the
antipode in terms of affinity and only mildly affected
5-HTP accumulation at the highest dose tested (35 µmol/
kg sc). Similarly, (1S,2R)-7l failed to produce a full-
blown 5-HT behavioral syndrome.
Exp er im en ta l Section
Ch em istr y. Gen er a l Com m en ts. Melting points (uncor-
rected) were determined in open glass capillaries on a Thomas-
Hoover apparatus. 1H NMR spectra were recorded on a J EOL

1490 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7
Valga˚rda et al.
F igu r e 1. Effect of (1R,2R)-7j, (1S,2S)-7j, (1R,2S)-7l, (1S,2R)-7l, and (1R,2S)-1 on cerebral 5-HT synthesis in rats. Reserpin-
pretreated rats (5 mg/kg sc, 18-20 h before the experiment) were given 0.35, 3.5, or 35 µmol/kg sc of (1R,2R)-7j, (1S,2S)-7j,
(1R,2S)-7l, (1S,2R)-7l, or (1R,2S)-1 60 min, and NSD1015 (100 mg/kg sc) 30 min before death; controls received NaCl and NSD1015
at corresponding time intervals. Shown are the 5-HTP contents (ng/g tissue) in limbic forebrain (a), striatal (b), and cortical (c)
brain tissue samples, means ( SEM of two to seven observations. Vertical figures inside the bars depict doses of the test compounds
(0.35-35 µmol/kg sc). *p e 0.05 vs corresponding NaCl control values.
filtered, and concentrated to afford pure 5c: 1H NMR (CDCl3)
Ta ble 4. 5-HT Behavioral Effects of (1R,2R)-7j, (1S,2S)-7j,
(1R,2S)-7l, (1S,2R)-7l, and (1R,2S)-1 in Reserpinized Ratsa
δ 7.24-7.16 (m, 1 H), 7.10-6.95 (m, 3 H), 2.75 (ddd, J 1 ) 4.1
Hz, J 2 ) 7.0 Hz, J 3 ) 9.5 Hz, 1 H), 1.95 (ddd, J 1 ) 4.1 Hz, J 2
dose, µmol/kg sc
) 4.8 Hz, J 3 ) 8.3 Hz, 1 H), 1.67 (ddd, J 1 ) 4.8 Hz, J 2 ) 4.7
treatment
control
0
0.35
3.5
35
Hz, J 3 ) 9.5 Hz, 1 H), 1.45 (ddd, J 1 ) 4.7 Hz, J 2 ) 7.0 Hz, J 3
) 8.3 Hz, 1 H); 13C NMR (CDCl3) δ 180.1, 161.7 (d, J ) 246.4
Hz), 128.2 (d, J ) 8.4 Hz), 127.0 (d, J ) 4.2 Hz), 126.1, 124.1
(d, J ) 3.5 Hz), 115.4 (d, J ) 21.6 Hz), 22.7 (d, J ) 1.4 Hz),
20.8 (d, J ) 4.9 Hz), 16.2.
0 (0-0)
7
(1R,2R)-7j
(1S,2S)-7j
(1R,2S)-7l
(1S,2R)-7l
(1R,2S)-1
0 (0-0)
2
0 (0-0)
1 (0-1)
3
3
0 (0-0)
3
0 (0-0)
3
1 (1-2)
5
4 (2-5)
3
0 (0-0)
4
4 (3-5)
4
0 (0-0)
3
(1S,2S)-tr a n s-2-(2-Th ien yl)cyclopr opan ecar boxylic Acid
[(1S,2S)-5j]. Meth od IV. Titanium isopropoxide (6.0 mL, 21
mmol) was added to a solution of (+)-98a (7.41 g, 21 mmol) in
benzyl alcohol (40 mL). The solution was heated (150 °C, oil
bath) for 45 min and then allowed to cool to room temperature.
The solution was concentrated and the residue was purified
on a silica column eluted with ether/petroleum ether (1:9),
yielding 3.62 g of a mixture of the benzyl and the isopropyl
esters. The mixture was dissolved in MeOH (30 mL), and 2
M aqueous NaOH (30 mL) was added. The resulting solution
was stirred at room temperature for 6 h and finally heated to
40 °C (oil bath) for 20 min in order to dissolve the remaining
substrate. The solution was concentrated, and the residue was
washed with CH2Cl2 (3 × 30 mL), EtOAc (3 × 30 mL), and
ether (3 × 30 mL), acidified with 5 M aqueous HCl, extracted
with CH2Cl2 (3 × 30 mL), dried (MgSO4), filtered, and
concentrated to yield 2.11 g (60%) of (1S,2S)-5j: 1H NMR
(CDCl3) δ 7.11 (dd, J 1 ) 1.3 Hz, J 2 ) 5.1 Hz, 1 H), 6.91 (dd, J 1
) 3.6 Hz, J 2 ) 5.0 Hz, 1 H), 6.84 (m, 1 H), 2.78 (ddd, J 1 ) 4.0
Hz, J 2 ) 6.6 Hz, J 3 ) 9.2 Hz, 1 H), 1.94 (ddd, J 1 ) 4.0 Hz, J 2
) 5.2 Hz, J 3 ) 8.4 Hz, 1 H), 1.69 (ddd, J 1 ) 4.6 Hz, J 2 ) 5.2
Hz, J 3 ) 9.2 Hz, 1 H), 1.42 (ddd, J 1 ) 4.6 Hz, J 2 ) 6.6 Hz, J 3
a
Shown are the summed “5-HT behavioral syndrome” scores
(median, range in brackets; n observations) obtained in a 60-s
rating session, starting 30 min after administration of the test
compounds (0.35-35 µmol/kg sc) in reserpine-pretreated rats (5
mg/kg sc, 18-20 h before experiment).
concentrated. The crude product was purified on a silica
column eluted with ether/petroleum ether (1:6). The resulting
ester was dissolved in MeOH (10 mL), and 2 M aqueous NaOH
(5 mL) was added. The solution was stirred at room temper-
ature for 2 h. The MeOH was evaporated, and the remaining
solution was diluted with H2O (15 mL), washed with ether (20
mL), acidified with 5 M aqueous HCl, and extracted with ether
(3 × 20 mL). The combined organic layers were dried (MgSO4),

trans-2-Aryl-N,N-dipropylcyclopropylamines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7 1491
) 8.4 Hz, 1 H); 13C NMR (CDCl3) δ 179.5, 143.4, 126.9, 124.1,
123.4, 24.8, 22.3, 18.3.
(1R,2R)-tr a n s-2-(2-Th ien yl)cyclop r op a n eca r b oxylic
Acid [(1R,2R)-5j]. The acid (1R,2R)-5j was prepared from
(-)-97a (6.62 g, 24 mmol) yielding 3.08 g (78%) of pure
carboxylic acid.
was dissolved in dry 2-(trimethylsilyl)ethanol (5 mL), and the
solution was heated to 60 °C (bath temperature) for 14 h. The
crude carbamate was purified on a silica column eluted with
ether/petroleum ether (1:2). The purified carbamate was
treated with tetrabutylammonium fluoride (1 M solution in
THF, 19 mL, 19 mmol) at 50 °C for 19 h. H2O (50 mL) was
added, and the stirring was discontinued after an additional
15 min. The mixture was concentrated, and the remaining
water solution was acidified with 1 M aqueous HCl, washed
with CH2Cl2 (50 mL), alkalinized [Na2CO3(s)], and extracted
with EtOAc3 (3 × 100 mL). The combined organic layers were
dried (K2CO3) and concentrated. The crude primary amine
was converted into the oxalate and recrystallized to afford
(1R,2R)-6j‚C2O4H2: 1H NMR (CD3OD) δ 7.17 (dd, J 1 ) 1.3 Hz,
J 2 ) 5.1 Hz, 1 H), 6.91-6.83 (m, 2 H), 2.74 (ddd, J 1 ) 3.5 Hz,
tr a n s-2-(2,3-Dich lor op h en yl)cyclop r op yla m in e (6g).
Meth od V. Diphenyl phosphorazidate (1.93 mL, 9.0 mmol)
and triethylamine (1.25 mL, 12 mmol) was added to a solution
of 5g (2.00 g, 8.2 mmol) in dry t-BuOH (20 mL). The resulting
solution was stirred at 90 °C (bath temperature) for 42 h and
was then concentrated. The residue was partitioned between
10% aqueous Na2CO3 (40 mL) and ether (4 × 40 mL). The
combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was purified on a silica column
eluted with ether/petroleum ether (1:4). The resulting tert-
butyl carbamate was treated with 1 M aqueous HCl (50 mL)
at 100 °C overnight. The solution was washed with ether (3
× 40 mL), and saturated aqueous K2CO3 was added to pH
about 10. The mixture was extracted with EtOAc (3 × 70 mL).
The combined organic layers were dried (K2CO3), filtered, and
concentrated. The resulting primary amine was converted into
the hydrochloride and recrystallized to afford 6g‚HCl: 1H NMR
(CD3OD) δ 7.46 (d, J ) 7.9 Hz, 1 H), 7.27 (dd, J 1 ) J 2 ) 7.9
Hz, 1 H), 7.12 (d, J ) 7.9 Hz, 1 H), 2.86 (ddd, J 1 ) 3.8 Hz, J 2
) 4.6 Hz, J 3 ) 7.9 Hz, 1 H), 2.64 (ddd, J 1 ) 3.8 Hz, J 2 ) 6.6
Hz, J 3 ) 10.2 Hz, 1 H), 1.51 (ddd, J 1 ) 4.6 Hz, J 2 ) 6.6 Hz, J 3
) 10.2 Hz, 1 H), 1.41 (ddd, J 1 ) 6.6 Hz, J 2 ) 6.6 Hz, J 3 ) 7.9
Hz, 1 H); 13C NMR (CD3OD) δ 139.6, 134.3, 133.9, 130.2, 128.9,
127.4, 31.6, 21.8, 13.1.
t r a n s-2-(5-F lu o r o -2-m e t h o x y p h e n y l)c y c lo p r o p y l-
a m in e (6h ). Meth od VI. A mixture of 5h (4.6 g, 21.9 mmol),
triethylamine (4.27 mL, 30.6 mmol), and ethyl chloroformate
(3.14 mL, 32.8 mmol) in dry acetone (150 mL) was stirred at
-10 °C, and a solution of NaN3 (2.42 g, 37.2 mmol) in H2O (10
mL) was added after 2.5 h. The stirring was discontinued after
an additional 2 h. The resulting suspension was poured into
cold H2O (220 mL) and was extracted with toluene (4 × 100
mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated to about 50% of the volume to
remove remaining traces of H2O. The resulting solution was
heated (90 °C bath temperature) until the evolution of nitrogen
ceased (about 3 h), and the solution was concentrated. The
resulting isocyanate was dissolved in dry t-BuOH (50 mL), and
the solution was refluxed for 23 h. The reaction mixture was
concentrated, and the crude tert-butyl carbamate was purified
on a silica column eluted with ethyl acetate/hexane (1:3). The
carbamate was hydrolyzed by use of 1 M aqueous HCl (200
mL) at 100 °C (both temperature) for 15 h. The solution was
washed with ether (3 × 100 mL), alkalinized with saturated
aqueous K2CO3, and extracted with EtOAc (4 × 200 mL). The
combined organic layers were dried (K2CO3), filtered, and
concentrated. The oily primary amine was converted into the
hydrochloride and recrystallized to afford pure 6h ‚HCl: 1H
NMR (CD3OD) δ 6.95-6.93 (m, 2 H), 6.74 (d, J ) 9.0 Hz, 1
H), 3.86 (s, 1 H), 2.79 (ddd, J 1 ) 3.6 Hz, J 2 ) 4.2 Hz, J 3 ) 7.8
Hz, 1 H), 2.53 (ddd, J 1 ) 3.6 Hz, J 2 ) 6.9 Hz, J 3 ) 10.1 Hz, 1
H), 1.38 (ddd, J 1 ) 4.2 Hz, J 2 ) 6.7 Hz, J 3 ) 10.1 Hz, 1 H),
1.32 (ddd, J 1 ) 6.9 Hz, J 2 ) 6.7 Hz, J 3 ) 7.8 Hz, 1 H); 13C
NMR (CD3OD) δ 158.3 (d, J ) 237 Hz), 155.8 (d, J ) 2.1 Hz),
129.6 (d, J ) 7.7 Hz), 114.6 (d, J ) 23.0 Hz).
J 2 ) 4.4 Hz, J 3 ) 7.9 Hz, 1 H), 2.47 (dddd, J 1 ) 0.75 Hz, J 2
)
3.5 Hz, J 3 ) 6.4 Hz, J 4 ) 9.9 Hz, 1 H), 1.40 (ddd, J 1 ) 4.4 Hz,
J 2 ) 6.6 Hz, J 3 ) 9.9 Hz, 1 H), 1.22 (ddd, J 1 ) 6.4 Hz, J 2 ) 6.6
Hz, J 3 ) 7.9 Hz, 1 H); 13C NMR (CD3OD) δ 166.7, 143.2, 128.0,
125.3, 124.8, 32.6, 17.8, 14.7.
tr a n s-2-(5-F lu or o-2-m eth oxyp h en yl)-N,N-d ip r op ylcy-
clop r op yla m in e (7h ). Meth od VIII. A mixture of 6h ‚HCl
(0.5 g, 2.3 mmol), 1-iodopropane (0.54 mL, 5.5 mmol), and
finely ground K2CO3 (1.14 g, 8.3 mmol) in MeCN (10 mL) was
stirred at room temperature for 4 days. Ether (15 mL) was
added, and insoluble material was removed by filtration. The
filtrate was concentrated, and the residue was chromato-
graphed on an alumina column eluted with ether/petroleum
ether (1:16). The resulting tertiary amine was converted into
the hydrochloride and recrystallized to afford 7h ‚HCl as a
white solid: 1H NMR (CD3OD, 90 MHz) δ 7.00-6.92 (m, 2 H),
6.75 (d, J ) 9.4 Hz, 1 H), 3.88 (s, 1 H), 3.39-3.20 (m, 4 H),
3.00-2.64 (m, 2 H), 1.97-1.50 (m, 6 H), 1.03 (dd, J 1 ) 7.2 Hz,
J 2 ) 7.2 Hz, 1 H); 13C NMR (CD3OD) δ 158.4 (d, J ) 237 Hz),
155.8 (d, J ) 2.1 Hz), 128.7 (d, J ) 7.7 Hz), 115.0 (d, J ) 23.0
Hz), 114.3 (d, J ) 24.4 Hz), 112.6 (d, J ) 8.4 Hz), 57.7 (2 C’s),
56.5, 46.0, 18.5 (3 C’s), 12.7, 11.5 (2C’s).
tr a n s-2-(5-F lu or o-2-h yd r oxyp h en yl)-N,N-d ip r op ylcy-
clop r op yla m in e (71). Meth od IX. A stirred solution of 7h ‚
HCl (0.15 g, 0.50 mmol) in 48% aqueous HBr (10 mL) was
heated for 2 h (120 °C bath temperature). The solution was
concentrated, and the residue was partitioned between satu-
rated aqueous NaHCO3 (20 mL) and ether (20 mL). The
aqueous layer was extracted with ether (3 × 30 mL), and the
combined organic layers were dried (Na2SO4, filtered, and
concentrated. The crude 71 was converted into the hydro-
chloride and recrystallized to afford 71‚HCl as a white solid:
1H NMR (CD3OD, 90 MHz) δ 6.85-6.60 (m, 3 H), 3.42-3.23
(m, 4 H), 3.00-2.61 (m, 2 H), 1.98-1.50 (m, 6 H), 1.02 (dd, J 1
) 7.2 Hz, J 2 ) 7.2 Hz, 6 H); 13C NMR (CD3OD) δ 157.7 (d, J
) 235 Hz), 153.6 (d, J ) 1.4 Hz), 126.4 (d, J ) 7.7 Hz), 116.4
(d, J ) 8.3 Hz), 115.0 (d, J ) 23.0 Hz), 114,2 (d, J ) 24.3 Hz),
57.6 (2 C’s), 45.8, 18.8, 18.4 (2 C’s), 12.5, 11.3 (2 C’s).
P h a r m a cology. An im a ls. Male Sprague-Dawley rats (B
& K Universal, Sollentuna, Sweden), weighing 250-300 g,
were used throughout the studies. The rats were housed five/
cage under standardized environmental conditions (tempera-
ture 22-23 °C; humidity 55-60%; 14/10 light/dark cycle, lights
on at 6 am; rat chow and tap water allowed ad lib) for at least
1 week after the arrival until used in the experiments.
Reserpine pretreatment (5 mg/kg, sc) was given to all animals
18-20 h before start of the experiments (cf. below).
(1R,2R)-tr a n s-2-(2-Th ien yl)cyclop r op yla m in e [(1R,2R)-
6j]. Meth od VII. Ethyl chloroformate (2.3 mL, 24 mmol) was
added to a cooled solution (-10 °C) of (1R,2R)-5j (2.9 g, 17
mmol) and triethylamine (2.9 mL, 21 mmol) in dry acetone
(100 mL). After 2 h, a solution of NaN3 (1.68 g, 26 mmol) in
H2O (5 mL) was added to the stirred solution. The stirring
was discontinued after 1 h, and H2O (100 mL) was added. The
solution was concentrated, and the remaining H2O solution
was extracted with ether (4 × 100 mL). The combined organic
layers were dried (MgSO4), filtered, and concentrated. The
residue was dissolved in toluene (150 mL). The solution was
concentrated to about half the volume in order to remove
remaining traces of H2O and was then heated (90 °C bath
temperature) until the evolution of N2 ceased (2 h). The
volatiles were evaporated in vacuo. The resulting isocyanate
Dr u gs. The compounds to be tested were dissolved in
physiological (0.9%, w/v) saline immediately before use, oc-
casionally with the addition of a few drops of glacial HOAc
and/or moderate heating to obtain complete dissolution. Re-
serpine (Ciba, Basel, Switzerland) was dissolved in a few drops
of glacial HOAc and made up to volume with 5.5% glucose (w/
v). All drugs, including reserpine and NSD1015 (Sigma, St.
Louis, MO), were subcutaneously injected into the neck region,
in a volume of 5 mL/kg.
Bioch em istr y. The biochemical experiments, including
brain dissections and HPLC determinations (electrochemical
detection) of tissue contents of DOPA and 5-HTP, were carried
out essentially according to methods detailed elsewhere.25,26
Empirically, the maximum decrease of cerebral 5-HTP values

1492 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7
Valga˚rda et al.
obtained with a direct-acting 5-HT1A receptor agonist (e.g., 3)
is about 50% from control values under conditions equivalent
to those used in the present experiments (see ref 4c).
Su p p or tin g In for m a tion Ava ila ble: Selected 1H NMR
chemical shifts and coupling constants of 6a -k (1 page).
Ordering information is given on any current masthead page.
Beh a vior . The occurrence and intensity of flattened body
posture, forepaw treading, and hindlimb abduction was scored
for 60 s at the 30-min time point following test drug admin-
istration, using an intensity-based rating scale, where 0 )
absent, 1 ) equivocal, 2 ) definite, and 3 ) intense;27 i.e, the
maximum summed score for the total set of behavioral items
was 9. For reference, a dose of 0.1 µmol/kg (sc) of (R)-3 which
causes a near-maximal postsynaptic 5-HT1A behavioral activa-
tion yields summed scores 8-9 using this approach under
similar conditions (cf. ref 27). Observations of other effects of
the drugs on behavior were also simultaneously noted, though
not quantified.
Refer en ces
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Sta tistics. The biochemical data are expressed in percent
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ANOVA, followed by Fisher’s protected least-significant-dif-
ference test (PLSD), was used for statistical comparisons of
drug-treated groups with controls. The behavioral data are
expressed as medians (range). Probability levels e5% were
considered statistically significant.
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5-HT1A Recep tor Bin d in g Assa y. Male Sprague-Dawley
rats (weighing about 200 g) were decapitated, and the cortex
and hippocampus were dissected. The tissues (600-900 mg)
from each rat were immediately homogenized in 15 mL of ice-
cold 50 mM Tris-HCl buffer containing 4.0 mM CaCl2 and 5.7
mM ascorbic acid, pH 7.5, with an Ultra Turrax (J anke and
Kunkel, Staufen, FRG) for 10 s. After centrifugation for 12.5
min at 17000 rpm (39800g) in a Beckman centrifuge with a
chilled J A-17 rotor (Beckman, Paulo Alto, CA), the pellets were
resuspended in the same buffer, and homogenization and
centrifugation were repeated. The pellets from at least six rats
were again suspended in the buffer, pooled, homogenized, and
stored on ice for 1-4 h. The tissue homogenate was diluted
to 10 mg/1.25 mL with the buffer, incubated for 10 min at 37
°C, and supplied with 10 µM pargylin (Sigma, St. Louis, MO)
followed by reincubation for 10 min.
Incubation mixtures (2 mL) contained 1-300 nM test
compound (diluted in 50 mM Tris-HCl containing 5.7 mM
ascorbic acid, pH 7.5), 2 nM [3H]-8-OH-DPAT ([3H]-8-hydroxy-
2-(dipropylamino)tetralin hydrobromide), 31.60 Ci/mmol, New
England Nuclear, Dreieich, Germany, and Research Biochemi-
cals, Wayland, MA), 5 mg/mL tissue homogenate in 50 mM
Tris-HCl buffer containing 4.0 mM CaCl2 and 5.7 mM ascorbic
acid, pH 7.5. Binding experiments were started by the
addition of tissue homogenate followed by incubation at 37 °C
for 10 min. The incubation mixtures were filtered through
Whatman GF/B glass filters with a Brandel Cell Harvester
(Gaithersburg, MD). The filters were washed twice with 5 mL
of ice-cold 50 mM Tris-HCl buffer, pH 7.5, and counted with 5
mL of Packard Ultima Gold in a Beckman LS 3801 scintillation
counter. Nonspecific binding was measured by the addition
of 10 µM 5-HT‚HCl to the reaction mixture. The binding data
were processed by nonlinear least squares computer analysis.28
A Kd value of 1.4 nM for 8-OH-DPAT binding was obtained
from the saturation experiments and was used to calculate
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of the standard error of the estimate of Ki. Four of the
compounds in Table 4 [(1S,2R)-7h , (1R,2S)-7h , (1S,2R)-7l, and
(1R,2S)-7l] were assayed for 5-HT1A binding using a slightly
modified procedure.29
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Ack n ow led gm en t. Support for this study was pro-
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