glennon.partial.agonists, biotransformation
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3074
J. Med. Chem.
2000,
43,
3074
-
3084
1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes as 5-HT
2A
Partial Agonists
Cynthia S. Dowd,
†,#
Katharine Herrick-Davis,
‡
Christina Egan,
‡
Ann DuPre,
‡
Carol Smith,
‡
Milt Teitler,
‡
and
Richard A. Glennon*
,†
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University,
Richmond, Virginia 23298-0540, and Center for Neuropharmacology and Neuroscience,
Albany Medical College, Albany, New York 12208
Received December 13, 1999
Phenylalkylamines such as 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB;
1a
) and
its corresponding iodo derivative DOI (
2
) are commonly used 5-HT
2
serotonin agonists. Previous
studies have established that the 2,5-dimethoxy substitution pattern found in these compounds
is optimal for high affinity at 5-HT
2A
receptors and that substituents at the 4-position can
modulate affinity over a wide range. We have previously shown, however, that when the
4-position is substituted with a 3-phenylpropyl substituent (i.e.,
3
), the compound binds with
an affinity comparable to that of
1a
but that it possesses 5-HT
2A
antagonist character. The
present study examined the structure
affinity relationships of
3
, and the results were very
much unexpected. That is, the 2,5-dimethoxy substitution pattern of
3
is not required for high
affinity. Either of the two methoxy groups can be removed without untoward effect on affinity,
and relocation of the methoxy substituents actually enhances affinity by as much as an order
of magnitude. None of the compounds displayed more than 20-fold selectivity for 5-HT
2A
over
5-HT
2C
receptors. In addition, several were demonstrated to act as 5-HT
2A
partial agonists. As
such, the results of this study suggest that the structure
-
affinity relationships of phenyl-
alkylamines as 5-HT
2A
ligands now be reinvestigated in greater detail.
-
The 5-HT
2
family of serotonin (5-HT) receptors has
been implicated in cardiovascular function, thermoregu-
lation, schizophrenia, depression, anxiety, and eating
disorders (reviewed in refs 1
3). Considerable literature
exists on the search for, and development of, novel
5-HT
2
agentssin particular, of novel 5-HT
2
antagonists
(reviewed in refs 3 and 4). Perhaps one reason there
has been less emphasis on 5-HT
2
agonists is that agents
with demonstrated 5-HT
2
agonist character have been
shown to be hallucinogenic in humans.
5
Phenylalkyl-
amines such as 1-(4-bromo-2,5-dimethoxyphenyl)-2-amino-
propane (DOB;
1a
) and 1-(2,5-dimethoxy-4-iodophenyl)-
2-aminopropane (DOI;
2
) represent well-established
5-HT
2
receptor ligands, and [
3
H]DOB and [
125
I]DOI have
been introduced as radioligands to label 5-HT
2
receptors.
Both DOB and DOI are considered 5-HT
2
agonists,
2
and
both are psychoactive in humans.
6
-
24 nM).
7,10
Interestingly however, unlike DOB, compound
3
was
found to act as a 5-HT
2A
antagonist in a phospho-
inositide hydrolysis assay.
10
As such, compound
3
represented the first example of a DOB-like phenyl-
alkylamine with 5-HT
2
antagonist character. It has been
proposed that although 5-HT
2A
agonists and antagonists
might share a common amine binding site (i.e., an
aspartate moiety in transmembrane helix III), they
otherwise appear to utilize different receptor binding
features (reviewed in ref 11). The possibility exists, then,
that
3
binds at 5-HT
2A
receptors in a somewhat different
fashion than DOB (
1a
). If such is the case, the structure
affinity comparable to that of
R
(
-
)DOB (
K
i
)
-
affinity relationships for the binding of these agents at
5-HT
2
receptors have been investigated in some de-
tail.
2,7,8
For example, it has been reported that the
presence of the 2,5-dimethoxy pattern is optimal for
5-HT
2
binding, and that removal of either of the meth-
oxy groups of DOB results in a dramatic decrease in
affinity.
9
During the course of our investigations with phenyl-
alkylamines, we prepared the 4-(3-phenylpropyl) de-
rivative
3
.
7
Compound
3
was found to bind at 5-HT
2A
receptors with high affinity (
K
i
The structure
-
affinity requirements of
3
might be different than those
of DOB. This prompted the present investigation. The
purpose of this study, then, was to examine the struc-
ture
affinity requirements for the binding of
3
-type
compounds at 5-HT
2A
receptors. Because few compounds
display selectivity for 5-HT
2A
versus 5-HT
2C
receptors,
5-HT
2C
binding data were also obtained.
-
)
10 nM) and with an
* Address correspondence to Dr. Richard A. Glennon, Department
of Medicinal Chemistry, School of Pharmacy, Box 980540, Virginia
Commonwealth University, Richmond, VA 23298-0540. Phone: 804-
828-8487. Fax: 804-828-7404. E-mail: glennon@hsc.vcu.edu.
†
Virginia Commonwealth University.
‡
Albany Medical College.
#
Present address: School of Medicine, University of Pennsylvania,
Philadelphia, PA 19104-6100.
Chemistry
Compound
3
was prepared as previously reported.
7
Compounds
4
-
6
(Scheme 1) were prepared in a similar
10.1021/jm9906062 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/14/2000
1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes
Journal of Medicinal Chemistry, 2000, Vol. 43, No. 16
3075
Scheme 1
a
a
Reagents and conditions: (a) phenylacetyl chloride or hydrocinnamoyl chloride, TiCl
4
,CH
2
Cl
2
; (b) H
2
, 10% Pd/C, HOAc, 70% HClO
4
,
(c) 15% NaOH, MeOH; (d) ICl, NaI, HOAc, NaOH; (e) 4-(phenyl)butyn-1-yl cuprate, pyridine; (f) H
2
, 10% Pd/C, MeOH; (g) 15% NaOH,
MeOH.
manner. That is, beginning with the
N
-trifluoroacetyl-
protected phenylalkylamines
28
and
29
, Friedel
Scheme 2
a
-
Crafts
acylation provided the 4-acyl analogues
30
32
. Acyla-
tions of this type have been shown to occurs exclusively
at the 4-position.
12
Catalytic reduction of the ketone and
subsequent deprotection afforded compounds
4
-
6
. Com-
pounds
7
and
8
were prepared in a somewhat different
manner (Scheme 1). The phenylalkylamines
28
and
29
were iodinated to give
36
and
37
, respectively. We have
previously reported the synthesis of
37
.
13
The iodo
derivatives were reacted with 4-(phenyl)butyn-1-yl cu-
prate to give the corresponding alkynes
38
and
39
,
which were then catalytically reduced to
40
and
41
,
respectively. Deprotection afforded compounds
7
and
8
.
Compounds
9
and
10
, chloro and methoxy analogues of
3
, were obtained using a reaction similar to that used
for the preparation of
4
except that a Wolff
-
Kishner
reduction was used to reduce the intermediate ketone
leading to
9
.
Compounds
12
,
13
,
17
, and
18
were prepared via a
common route (Scheme 2) employing a Suzuki-type
reaction
14
with the appropriately substituted triflates
(i.e.,
42
,
47
,or
50
) as starting material. Reaction of the
triflates with 9-(3-phenylpropyl)-9-BBN (
45
) and 1,1
-
-
bis(diphenylphosphinoferrocene)Pd afforded phenylpro-
pylbenzaldehydes
43
,
48
, and
51
. The benzaldehyde
derivatives were converted to their nitrostyrenes and
reduced with LiAlH
4
to the required amines. Compound
14
was obtained by introduction of a 3-(3-phenylpropyl)
group to 1,2-dimethoxybenzene, followed by formylation
and elaboration to the amine as described above. In
contrast, compound
15
was prepared directly from the
preformed phenylisopropylamine
54
by an acylation-
reduction
¢
-bis(diphenylphosphino-
ferrocene)Pd, THF, NaOH; (b) CH
3
NO
2
or C
2
H
5
NO
2
,NH
4
OAc, ¢;
(c) LiAlH
4
, THF, ¢.
a
Reagents and conditions: (a)
45
, 1,1
¢
obtained from 3,5-dimethoxybenzaldehyde (
53
) via a
literature procedure.
15
Compound
53
was also used to
obtain the phenylpropyl derivative
57
which was sub-
sequently formylated and elaborated to the desired
amine
16
(Scheme 3).
reaction
(Scheme
3).
Compound
54
was
3076
Journal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Dowd et al.
Scheme 3
a
a
Reagents and conditions: (a)
i.
C
2
H
5
NO
2
,NH
4
OAc, ¢;
ii.
LiAlH
4
, THF, ¢; (b)
i.
(CF
3
CO)
2
O, CH
2
Cl
2
;
ii.
hydrocinnamoyl chloride,
TiCl
4
,CH
2
Cl
2
; (c)
i.
H
2
, 10% Pd/C, 70% HClO
4
, HOAc;
ii
. 15% NaOH, MeOH; (d) Mg, PhCH
2
CH
2
Br, Et
2
O; (e) TMSCl, MeCN, NaI, Et
2
O;
(f) nBuLi, DMF, THF; (g)
i.
C
2
H
5
NO
2
,NH
4
OAc, ¢;
ii.
LiAlH
4
, THF, ¢.
Table 1.
5-HT
2A
and 5-HT
2C
Serotonin Receptor Binding Data
for Derivatives of
3
might enhance affinity whereas introduction of a meth-
oxy group (i.e., compound
10
) might have no effect.
These compounds would additionally assist in exploring
the influence of varied electronic character of the
terminal phenyl ring on 5-HT
2
binding. Both
9
(
K
i
)
12
nM) and
10
(
K
i
28 nM) were found to bind with an
affinity comparable to that of
3
. All of the changes
shown in Table 1 had minimal effect on 5-HT
2A
receptor
affinity.
Of major interest was the role of the 2,5-dimethoxy
groups of
3
on 5-HT
2A
affinity because this substitution
pattern is generally considered optimal for high affinity.
Interestingly, removal of either the 5-methoxy group
(i.e.,
12
;
K
i
)
receptor affinity;
K
i
, nM (SEM)
5-HT
2A
selectivity
a
n
R
Z
5-HT
2A
5-HT
2C
4
2
-H
-H
37 (3)
76 (6)
2.0
5
2
-Me
-H
95 (5)
140 (20)
1.5
)
8 nM) or removal of the 2-methoxy group
6
3
-H
-H
150 (15)
28 (2)
0.2
(i.e.,
13
;
K
i
17 nM) resulted in retention of affinity
(Table 2). Even relocation of the two methoxy groups to
the 2,3-, 3,5-, and 2,6-positions (i.e., compounds
14
)
3
3
-Me
-H
30 (3)
50 (1)
1.7
7
4
-H
-H
115 (45)
25 (6)
0.2
8
4
-Me
-H
8 (1)
6 (1)
0.8
16
;
K
i
) 4 nM, 4 nM, and 3 nM, respectively) was tolerated.
In fact, the latter three compounds displayed ap-
proximately 10-fold higher affinity than
3
itself. Fur-
thermore, removal of the two methoxy groups (i.e.,
17
;
K
i
-
9
3
-Me
-Cl
12 (3)
16 (1)
1.3
10
3 -Me -OMe 28 (3) 24 (1) 0.9
a
Selectivity represented by 5-HT
2C
K
i
value/5-HT
2A
K
i
value.
Results and Discussion
5-HT
2A
Receptor Binding
. The study began by
examining the role of chain length and the necessity of
the
78 nM) only halved affinity, whereas the des-
methoxy analogue of
6
(i.e.,
18
;
K
i
)
60 nM) displayed
twice the affinity of its parent (
6
,
K
i
)
150 nM).
Apparently, the presence and location of the methoxy
groups are not as important for the binding of
3
as they
appear to be for DOB (
1a
)-type compounds.
Because most of the structure-affinity relationships
for DOB-type compounds were originally formulated a
decade ago on the basis of rat brain-homogenate binding
data, and because the present investigation employed
cloned 5-HT
2A
receptors, the affinities of some known
DOB analogues were reinvestigated. Table 3 shows that
DOB (
1a
;
K
i
)
30
nM) (Table 1). Shortening the propyl chain to an ethyl
chain (i.e.,
5
) reduced affinity by about 3-fold whereas
lengthening the chain to a
n-
butyl group (i.e.,
8
)
enhanced affinity by about the same amount. The
R
R
-methyl group on the 5-HT
2A
affinity of
3
(
K
i
)
-methyl substituent seems to have a different effect
depending upon chain length. That is, demethylation
of
5
(i.e.,
4
) resulted in a 3-fold increase in affinity,
whereas demethylation of
3
(i.e.,
6
) and demethylation
of
8
(i.e.,
7
) decreased affinity by nearly 5-fold and 15-
fold, respectively. Because the longer chain compound
8
displayed slightly higher affinity than
3
,itwas
thought that adding some lipophilic character to
3
in
the form of a lipophilic chloro group (i.e., compound
9
)
32 nM) binds with high affinity at these
5-HT
2A
receptors and that removal of the
)
R
-methyl
group (i.e.,
1b
;
K
i
16 nM) has little effect on affinity.
Removal of the 4-bromo group of
1a
and
1b
,asin
19
and
20
, reduces affinity by about 150- to 200-fold,
)
1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes
Journal of Medicinal Chemistry, 2000, Vol. 43, No. 16
3077
Table 2.
5-HT
2A
and 5-HT
2C
Serotonin Receptor Binding Data
for Methoxy-Modified Derivatives of
3
is the influence of the 4-(3-phenylpropyl) group on
5-HT
2A
affinity. Incorporation of this group enhances
the affinity of the monomethoxy-, dimethoxy-, and even
the unsubstituted phenylalkylamines. In particular,
each of the following conversions enhances affinity by
more than 1000-fold:
21
f
12
(1,250-fold),
23
f
14
(1070-fold),
24
f
15
(2500-fold), and
26
f
16
(
3000-
fold). For the 4-(3-phenylpropyl) series, 2,5-dimethoxy
substitution cannot be considered optimal. Monomethoxy
derivative
12
, and dimethoxy derivatives
14
>
-
16
, bind
with
K
i
values of
10 nM. Even the nonmethoxy
analogues
17
and
18
bind with affinities not much less
than that of
3
.
5-HT
2C
Receptor Binding
. For those compounds
examined in the present study, the structure
<
receptor affinity;
K
i
, nM (SEM)
5-HT
2A
selectivity
a
3
2,5-Di-OMe -Me 30 (3) 50 (1) 1.7
12
2-OMe -Me 8 (1) 89 (1) 11.1
13
5-OMe
b
-Me 17 (1) 135 (6) 7.9
14
2,3-Di-OMe -Me 4 (1) 79 (8) 19.8
15
3,5-Di-OMe -Me 4 (1) 40 (2) 10.0
16
2,6-Di-OMe -Me 3 (1) 39 (2) 13.0
17
H -Me 78 (6) 530 (19) 6.8
18
H -H 60 (6) 525 (65) 8.9
a
Selectivity represented by 5-HT
2C
K
i
value/5-HT
2A
K
i
value.
b
The 5-methoxy derivative actually represents the 3-methoxy-
substituted compound; the present terminology is used for ease
of discussion.
R
R¢
5-HT
2A
5-HT
2C
affinity
requirements for 5-HT
2C
binding are not very different
from those for 5-HT
2A
binding. Consequently, none of
the compounds displayed dramatic selectivity for one
population over the other. Compound
3
binds at 5-HT
2C
receptors with high affinity (
K
i
) 50 nM) and with <2-
fold selectivity for 5-HT
2A
receptors (Table 1). Shorten-
ing the propyl chain by a single methylene group (i.e.,
5
) decreases affinity by about 3-fold, whereas lengthen-
ing the chain by a methylene group (i.e.,
8
) enhances
affinity by about 8-fold. Removal of the
-
Table 3.
5-HT
2A
and 5-HT
2C
Serotonin Receptor Binding Data
for Simple Monomethoxy, Dimethoxy, and Nonmethoxy
Phenylalkylamine Analogues
-methyl group
has relatively little effect on 5-HT
2C
affinity. The only
change that seems to have less effect on 5-HT
2C
binding
than on 5-HT
2A
binding is the influence of the methoxy
groups. For example, although removal of one of the
methoxy groups of
3
has little effect on 5-HT
2C
affinity,
relocation of the 2,5-methoxy groups to the 2,3-, 3,5-,
or 2,6-positions does not show the affinity-enhancing
effect that it did at 5-HT
2A
receptors. Consequently,
compounds
14
R
receptor affinity;
K
i
, nM (SEM)
16
display about 10- to 20-fold selectiv-
ity for 5-HT
2A
receptors. Nevertheless, selectivity is not
remarkable.
PI Hydrolysis
. Several compounds were examined
for their 5-HT
2A
functional activity in a PI hydrolysis
assay, and all showed agonist actions. Compounds
examined (followed by apparent intrinsic activity) in-
clude the following:
3
(0.71 ( 0.08),
12
(0.63 ( 0.04),
13
(0.90 ( 0.02),
15
(1.09 ( 0.02), and
17
(0.48 ( 0.08).
That is, these compounds behaved either as partial or
full agonists relative to 5-HT. Because we had previ-
ously demonstrated that
3
can act as an antagonist, this
effect was examined in greater detail. Several concen-
trations of
3
were examined (Figure 1); 100 nM
3
was
without significant agonist activity, and even 1
í
M
3
produced only about 25% of the maximal 5-HT effect.
However, at a concentration of 10
í
M,
3
produced 71%
of the maximal agonist effect. It would appear, then,
that
3
is a 5-HT
2A
partial agonist. However, 10
í
M
3
plus 10
í
M ketanserin (a 5-HT
2
antagonist that reduces
the effect of 10
í
M 5-HT to basal levels; data not shown),
still produced 30% of the maximal possible effect (Figure
1). These results suggest that
3
is producing its effect
by a combination of a 5-HT
2
mechanism plus some other
ketanserin-insensitive mechanism. Because
15
ap-
peared to be a full agonist, it too was examined in the
absence and presence of ketanserin (Figure 2). At first
glance, it would seem that
15
is a full agonist; that is,
10
í
M
15
produced an effect comparable to that pro-
duced by 10
í
M 5-HT. However, 10
í
M
15
plus 10
í
M
ketanserin produced 43% of the maximal possible effect.
-
R
R¢
X
5-HT
2A
5-HT
2C
1a
2,5-Di-OMe
-Me
Br
32 (4)
64 (12)
1b
2,5-Di-OMe
-H
-Br
16 (1)
190 (90)
19
2,5-Di-OMe
-Me
-H
4 720 (1,150)
>
10 000
20
2,5-Di-OMe
-H
-H
3 000 (410)
5 520 (390)
21
2-OMe
-Me
-H
>
10 000
>
10 000
22
5-OMe
a
-Me
-H
>
10 000
>
10 000
23
2,3-Di-OMe
-Me
-H
4 280 (460)
>10 000
24
3,5-Di-OMe
-Me
-H
>10 000
>10 000
25
3,5-Di-OMe
-Me
-Br
210 (45)
570 (110)
26
2,6-Di-OMe
-Me
-H
>10 000
>10 000
>10 000
a
The 5-methoxy derivative actually represents the 3-methoxy-
substituted compound; the present terminology is used for ease
of discussion.
27
H
-Me
-H
>10 000
respectively. Removal of either of the methoxy groups
reduces the affinity of
19
; that is, the two individual
monomethoxy derivatives (i.e.,
21
and
22)
lack affinity
for 5-HT
2A
receptors. Relocation of the 2,5-dimethoxy
groups to the 3,5- or 2,6-positions (i.e.,
24
,
26
;
K
i
>
10 000 nM), and removal of both methoxy groups (i.e.,
27
;
K
i
10 000 nM), essentially abolishes affinity. We
previously reported that
27
binds with a
K
i
>
43 000
nM.
9
Reincorporation of a 4-bromo group (i.e.,
25
)
enhances the affinity of
24
. In general, these results are
qualitatively similar to what we have previously re-
ported: (a) monomethoxy phenylalkylamine derivatives
lack affinity, (b) dimethoxy derivatives lack affinity or
bind only with low affinity, and (c) substitution at the
4-position of 2,5-dimethoxy derivatives modulates af-
finity.
2,7
What is remarkable about the present results
)
3078
Journal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Dowd et al.
compounds; although this remains to be investigated in
detail, it is unlikely that stereochemical differences by
themselves can account for the observed variation in
5-HT
2A
affinity. None of the investigated compounds
displayed
20-fold selectivity for 5-HT
2A
versus 5-HT
2C
receptors. Several of the compounds were examined in
a 5-HT
2A
PI hydrolysis assay and were found to behave
as partial agonists. It now can be concluded that when
a 4-(3-phenylpropyl) substituent is present, the resulting
phenylalkylamine derivatives defy currently established
DOB-like structure
>
affinity relationships for 5-HT
2A
binding. The same may be true of certain other 4-alkyl-
or 4-(arylalkyl)-substituted derivatives, but this remains
to be determined. In retrospect, because the presence
of 2,5-dimethoxy substitution now has been demon-
strated to result in compounds that retain 5-HT
2
agonist
character, the structure
-
Figure 1.
SEM) of compound
3
, alone and in
combination with the 5-HT
2
antagonist ketanserin (KET), on
PI turnover. Basal
Effect (
(
activity relationships of phen-
ylalkylamines require reinvestigation.
-
10
í
M 5-HT. The
response to 5-HT was completely blocked by 10
í
M ketanserin
(data not shown). *
p
)
basal level; 5-HT
)
Experimental Section
A. Synthesis.
Melting points were determined with a
Thomas-Hoover melting point apparatus and are uncorrected.
Proton magnetic resonance (
1
H NMR) spectra were obtained
with a Varian Gemini 300 spectrometer, using tetramethyl-
silane as an internal standard. Infrared spectra were recorded
on a Nicolet 5ZDX FT-infrared spectrometer. Elemental
analysis was performed by Atlantic Microlab, Inc., and deter-
mined values are within 0.4% of theory. Unless otherwise
stated, amine salts were obtained and purified by the following
standard methods: (a) hydrochlorides: by the dropwise ad-
dition of a saturated, anhydrous solution of ethereal HCl into
a cold solution of the free base in anhydrous ether until
addition of ethereal HCl did not produce further precipitate;
(b) oxalates: by the dropwise addition of a solution of an excess
of oxalic acid in anhydrous ether into a cold solution of the
free base in anhydrous ether. Addition was terminated when
oxalic acid failed to produce more precipitate. Thin-layer
chromatography (TLC) was performed using silica gel-coated
GHIF plates (250
í
m, 2.5
<
0.05; **
p
<
0.01; ***
p
<
0.001 relative
to Basal (Student’s
t
-test).
10 cm, Analtech, Inc., Newark,
DE). Dry THF was obtained by distillation over sodium metal
and benzophenone. Dry CH
2
Cl
2
was obtained by distillation
over phosphorus pentoxide (P
2
O
5
). Most compounds shown in
Table 3 were available from previous studies or were resyn-
thesized using methods we had reported earlier and, with the
exception of
27
sulfate, were used as their HCl salts.
2-[2,5-Dimethoxy-4-(2-phenylethyl)phenyl]-1-amino-
ethane HCl (4).
A solution of
33
(0.18 g, 0.47 mmol) in MeOH
(15 mL) and 15% NaOH (15 mL) was heated at reflux for 2 h.
The MeOH was removed under reduced pressure, and the
basic solution was cooled to room temperature and extracted
with Et
2
O(3
Figure 2.
SEM) of compound
15
, alone and in
combination with the 5-HT
2
antagonist ketanserin (KET), on
PI turnover. Basal
Effect (
(
10
í
M 5-HT. The
response to 5-HT was completely blocked by 10
í
M ketanserin
(data not shown). *
p
)
basal level; 5-HT
)
<
0.001 relative to Basal (Student’s
t
-test).
Like
3
,
15
seems to be producing its agonist effects via
more than one mechanism. Compounds
3
and
15
might
best be classified as partial agonists in this assay.
Summary
. Although 2,5-dimethoxy substitution is
common to DOB (
1a
) and DOI-type 5-HT
2
agonists and
is thought to be an important factor for high affinity,
the present study provides the first evidence that this
dimethoxy pattern is not required for binding at this
receptor population. 1-[2,5-Dimethoxy-4-(3-phenylpro-
pyl)phenyl]-2-aminopropane (
3
;
K
i
30 mL). The ethereal solution was dried
(MgSO
4
) and evaporated under reduced pressure. The HCl salt
was formed and recrystallized from 2-PrOH to give 0.07 g
(46%) of
4
as a white powder; mp 197
-
198 °C.
1
H NMR
(D
2
O):
ä
2.86
2.89 (m, 6H, CH
2
), 3.13 (t, 2H, CH
2
), 3.66 (s,
3H, OCH
3
), 3.69 (s, 3H, OCH
3
), 6.72 (s, 1H, Ar
-
-
H), 6.85 (s,
1H, Ar
H); IR (KBr pellet): 2962
(NH
+
)cm
-1
. Anal. Calcd. for (C
18
H
24
ClNO
2
)C,H,N.
(
-
H), 7.14
-
7.28 (m, 5H, Ar
-
30 nM) binds at
5-HT
2A
receptors with an affinity comparable to that of
DOB (
K
i
)
)1-[2,5-Dimethoxy-4-(2-phenylethyl)phenyl]-2-amino-
propane HCl (5)
. Compound
5
was prepared in 47% overall
yield from
35
in the same manner used for the preparation of
4
. The HCl salt was recrystallized from 2-PrOH to give 0.10 g
of
5
;mp165
(
32 nM). However, unlike what is seen with
DOB,
9
removal of either one of the two methoxy groups
has little effect on 5-HT
2A
affinity. In fact, removal of
either of the two methoxy groups actually enhances
affinity. In addition, the location of these methoxy
groups is seemingly unimportant for binding. That is,
the 2,3-, 3,5-, and 2,6-dimethoxy analogues of
3
bind
with up to 10 times the affinity of
3
. Even removal of
both methoxy groups has little effect on affinity. Ster-
eochemistry (i.e., optical isomerism and regioisomerism)
may play a role in the binding of some of these
)
-
167 °C.
1
H NMR (D
2
O):
ä
1.20 (d, 3H, CH
3
),
2.79
3.57 (m, 1H, CH), 3.64 (s, 3H,
OCH
3
), 3.68 (s, 3H, OCH
3
), 6.70 (s, 1H, Ar
-
2.84 (m, 6H, CH
2
), 3.50
-
-
H), 6.81 (s, 1H,
Ar
H); IR (KBr pellet): 2892 (NH
+
)
cm
-1
. Anal. Calcd. for (C
19
H
26
ClNO
2
)C,H,N.
2-[2,5-Dimethoxy-4-(3-phenylpropyl)phenyl]-1-amino-
ethane HCl (6)
. Compound
6
was prepared from
34
in the
same manner used for the synthesis of
4
. The HCl salt was
recrystallized from 2-PrOH to give 0.08 g (45%) of the desired
-
H), 7.12
-
7.24 (m, 5H, Ar
-
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