Synthesis and pharmacological characterization of a series of geometrically constrained 5-HT2A/2C receptor ligands

Article abstract of DOI:10.1021/jm030064v

In studies of the SAR of phenethylamine-type serotonin 5-HT_2A receptor agonists, substituted conformationally constrained tetrahydronaphthofurans were designed to investigate the optimal conformation of the 2-aminoethyl moiety. These compounds

Full text of DOI:10.1021/jm030064v

3526
J . Med. Chem. 2003, 46, 3526-3535
Syn th esis a n d P h a r m a cologica l Ch a r a cter iza tion of a Ser ies of Geom etr ica lly
Con str a in ed 5-HT2A/2C Recep tor Liga n d s
J ames J . Chambers, J ason C. Parrish, Niels H. J ensen, Deborah M. Kurrasch-Orbaugh,
Danuta Marona-Lewicka, and David E. Nichols*
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences,
Purdue University, West Lafayette, Indiana 47907
Received February 11, 2003
In studies of the SAR of phenethylamine-type serotonin 5-HT2A receptor agonists, substituted
conformationally constrained tetrahydronaphthofurans were designed to investigate the optimal
conformation of the 2-aminoethyl moiety. These compounds were tested using in vitro assays
for affinity at 5-HT1A, 5-HT2A, and 5-HT2C receptors. The benzofuran-containing analogues, 6a
and 6b, had significantly higher affinity for the 5-HT receptors tested than did the benzodi-
hydrofuran-containing compounds, 4a , 4b, 5a , and 5b. The most potent compound (8-bromo-
6-methoxy-4,5-dihydro-3H-naphtho[1,8-bc]furan-5-yl)aminomethane, 6b, had Ki values for
displacement of [125I]-DOI from 5-HT2A and 5-HT2C cloned rat receptors of 2.6 and 1.1 nM,
respectively. Despite their high affinity, the compounds of this naphthofuran series lacked
high intrinsic activity at the 5-HT2A receptor as measured using the phosphoinositide hydrolysis
assay. The most potent compound in vitro, 6b, was tested in the two-lever drug discrimination
assay in rats trained to discriminate LSD from saline, and failed to substitute, a result typical
for compounds with low intrinsic activity. Thus, although conformational constraint has led to
high-affinity 5-HT2A ligands with partial agonist activity, all of the spatial and steric properties
of the ligand necessary for full receptor activation have not yet been identified.
In tr od u ction
rahydronaphthofurans.4 The compounds of this series
were considered to be “hybrid” structures of the hal-
lucinogenic arylalkylamine and ergoline families be-
cause it had been hypothesized since the late 1950s
that the A ring of LSD corresponds to the phenyl ring
of the arylalkylamines and that the 5-oxygen of aryl-
alkylamines serves as a bioisostere of the indole N-1
nitrogen of LSD. Thus, tetrahydronaphthofuran series
3 was hypothesized to mimic the A, B, and C rings of
LSD.
Conformational restriction of bioactive molecules is
a valuable tool for investigating the topographical and
chemical features of small-molecule binding sites. Re-
straint of flexible molecules into distinct conformations
often allows one to test the functional effects of a subset
of the total conformational space. Recently, for example,
we have discovered by use of a conformational-restric-
tion design method the optimal orientation for the 2,5-
dimethoxy groups of typical hallucinogenic arylalkyl-
amines (1, DOM, X ) CH3; DOB, X ) Br; DOTFM, X )
CH3).1-3 The optimal conformations parallel those where
the methyl groups are tethered to the phenyl ring in
the form of dihydrofuran rings as in compound 2.
The majority of the compounds in series 3, however,
exhibited rather low affinity for the 5-HT2A receptor, and
none of those compounds produced LSD-like effects in
a drug discrimination animal model believed to reflect
the subjective behavioral effects of hallucinogenic drugs.
One compound of series 3, the brominated syn analogue,
did, however, possess high affinity for the 5-HT2A
receptor but lacked an LSD-like behavioral effect in
animals.4 These results suggested that the hypothesized
structural correlation between the arylalkylamine and
ergoline families was incorrect. The high binding affinity
but lack of hallucinogen-like behavioral activity of the
syn brominated analogue of series 3 indicated that this
Further investigation of arylalkylamines in our labo-
ratory by the use of conformational restriction has
recently focused on the 2-aminoalkyl side chain.4 Con-
formationally restricted analogues of arylalkylamines
in which the 2-aminoalkyl side chain has been con-
strained by incorporation into a tethered ring system
have most recently focused on a series of 4-aminotet-
* To whom correspondence should be addressed. Address: Depart-
ment of Medicinal Chemistry and Molecular Pharmacology, RHPH
Pharmacy Building, Room 506C, Purdue University, West Lafayette,
IN 47907-1333. Phone: (765) 494-1461. Fax: (765) 494-1414. E-mail:
drdave@pharmacy.purdue.edu.
10.1021/jm030064v CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/04/2003

5-HT2A/ 2C Receptor Ligands
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16 3527
drug might be an antagonist and lack the ability to
activate the receptor.
We, therefore, abandoned the notion of structural
similarity between ergolines and phenethylamines and
considered a de novo approach. Specifically, new tet-
rahydronaphthofurans, compounds 4-6, were designed
on the basis of a molecular scaffold similar to that of
series 3 to alter the spatial orientation of the aminoethyl
moiety in the ligand. The compounds in the new series
were designed also to exploit knowledge we had gained
about the active orientation of the 2- and 5-alkoxy
substituents of arylalkylamines. Most importantly, we
decided to examine conformations of the aminoethyl
moiety that were distinctly out of the aromatic ring
plane (i.e., nonplanar).
F igu r e 1. Illustration of out-of-plane, anti-periplanar con-
formation for compounds 4b, 5b, and 6b compared to in-plane,
anti-periplanar naphthofuran syn-Br-3 as viewed from the 6,7-
edge of the molecule. The amino group is at the uppermost
top of each structure, with the bromine atom at the very
bottom. Hydrogen atoms have been omitted for clarity.
The alkoxy substituent of compounds 4-6 that cor-
responds to the 5-methoxy group of typical arylalky-
lamines is incorporated into an appended dihydrofuran
ring. The peri interaction between the 6-methoxy group
and the buttressing by the adjacent methylene forces
the aminomethyl to adopt a conformation that we
hypothesized might be near optimal. Thus, compounds
4-6 localize the basic amine moiety to a region of space
that is out of the plane defined by the phenyl ring.
Conformational restriction of the alkylamine was de-
signed to test the hypothesis that the 2-aminoalkyl side
chain of arylalkylamines adopts an anti-periplanar
conformation upon binding to the 5-HT2A receptor
agonist binding site. The hypothesis that the amine
must lie in an anti-periplanar conformation and out of
the plane of the phenyl ring is based, in part, on solution
NMR studies of amphetamine.5
Molecular modeling of compounds 4b, 5b, and 6b and
the compound that exhibited the highest 5-HT2A recep-
tor affinity of series 3, the syn brominated analogue,
revealed that compounds 4b, 5b, and 6b adopt an
energetically favored conformation that resembles closely
an anti-periplanar conformation (Figure 1). The three
compounds 4b, 5b, and 6b all position the basic amine
out of the plane of the phenyl ring (semiempirical
generated models using Spartan6 and AM-1 potentials).
Although syn brominated 3 can mimic an anti-peripla-
nar conformation as well, the basic amine is locked into
a position closer to the plane of the phenyl ring than
the compounds of the presently described series.
In addition to investigation of the optimal 2-ami-
noalkyl conformation, compounds 4-6 were designed to
probe the effect of aromatization of the dihydrofuran
ring. It was predicted, on the basis of previous work,2,3
that aromatization of the dihydrofuran ring would
increase the affinity and efficacy of these compounds
at the 5-HT2A receptor.
proposed series could be derived from a single interme-
diate, (()-4a , also one of the target compounds. The
nonaromatized compounds of this naphthofuran series
contain two stereocenters and thus two pairs of enan-
tiomers, the syn and anti racemates. A divergent
synthetic scheme was designed to generate separately
each enantiomeric pair. Various combinations of bro-
mination, N-protection/deprotection, aromatization, and
reduction of (()-4a were envisioned to generate the
remainder of the series from this divergent intermedi-
ate.
Synthesis of compounds (()-4, (()-5, and (()-6 (Scheme
1) commenced with the regioselective bromination of
4-methoxyphenol (7) to afford 8 utilizing a method
described by Curran et al.7 Substituted phenol 8 was
subsequently O-alkylated using Finkelstein conditions
with methyl 4-bromocrotonate (9) to yield 10. Utilization
of exactly 1 equiv of potassium carbonate and a reaction
temperature of 0 °C resolved difficulties associated with
the synthesis of this γ-aryloxycrotonate.8 The methyl
ester 10 was then subjected to radical reaction condi-
tions to effect ring closure and afford benzofuran (()-
11.9 Limitations imposed by the high-dilution require-
ments of typical radical reactions were overcome by
employing a reaction design that maintained a low
concentration of tributyltin hydride, thus resulting in
fewer side reactions. Benzofuran (()-11 was then sub-
jected to base hydrolysis to afford substituted acetic acid
(()-12.4 Next, (()-12 was converted to the acyl chloride
with oxalyl chloride and subsequently to diazoketone
(()-13 by reaction with diazomethane.4 Diazoketone (()-
13 was then subjected to Wolff rearrangement by
treatment with silver benzoate and triethylamine in
methanol to afford the homologated methyl ester (()-
14.10 Ester (()-14 was subsequently hydrolyzed with
base to afford propionic acid (()-15.
Ch em istr y
Retrosynthetic analysis of the target naphthofurans
4-6 revealed that all six racemic compounds of the
An alternative approach (Scheme 2) was also em-

3528 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16
Chambers et al.
Sch em e 1
Sch em e 2
4a confirmed the syn geometry of the product. It is
hypothesized that the selectivity observed in the cata-
lytic reduction of (()-21 arose from steric-induced facial
selectivity. The occurrence of facial selectivity in com-
pounds that have structures similar to styrene (()-21
has been observed and reported in the literature.16,17
Synthesis of the remaining target compounds of the
current naphthofuran series began with aromatic bro-
mination of (()-4a to afford the syn brominated product
(()-4b (Scheme 4). Next, a sample of (()-4b was
N-protected to afford (()-22. Selective oxidation of the
dihydrofuran ring of (()-22 was accomplished utilizing
reaction with exactly 1 equiv of DDQ in dioxane to afford
(()-23. Base hydrolysis was then employed to remove
the N-protecting group and liberate the product (()-6b.
Finally, a portion of (()-4a was N-protected as the
trifluoroacetamide to afford (()-24 (Scheme 5). Trifluo-
roacetamide (()-24 was subsequently oxidized utilizing
reaction with 1 equiv of DDQ to afford (()-25. The
N-protecting group of (()-25 was then removed by base
hydrolysis to afford (()-6a . A further review of literature
pertaining to facially selective hydrogenation suggested
that the two target anti products, (()-5a and (()-5b, of
the current series could be obtained by utilizing condi-
tions that favor catalyst coordination with the primary
amine of the substrate molecule.18-20 It was anticipated
that metal-mediated reduction in a nonpolar solvent
would enable the basic amine moiety of (()-6a to
interact electronically with the metal catalyst, and thus,
hydrogen delivery from the metal would occur on the
same face as the amino group, resulting in the anti
product (()-5a .20 Indeed, catalytic hydrogenation of
primary amine (()-6a in hexane proceeded as antici-
ployed to generate a larger quantity of propionic acid
(()-15. This synthetic route involved reduction of methyl
ester (()-11 to alcohol (()-16 using sodium aluminum
hydride, followed by protection of the alcohol to afford
tosylate (()-17.11 The tosylate group was then displaced
by reaction with potassium cyanide in ethanol to afford
(()-18, followed by base hydrolysis of the nitrile to
generate homologated acid (()-15.
Propionic acid (()-15 was then converted to the acyl
chloride and subjected to Friedel-Crafts conditions to
effect ring closure and afford tricyclic ketone (()-19
(Scheme 3).12,13 The ketone moiety of (()-19 was func-
tionalized utilizing reaction with trimethylsilyl cyanide
and zinc iodide in dichloromethane.14,15 The adduct that
was formed by this reaction could not be purified and
was reduced directly with sodium aluminum hydride to
afford amino alcohol (()-20. This alcohol was then
dehydrated using acidic conditions to yield substituted
aminomethylstyrene (()-21. Subsequently, catalytic
reduction of (()-21 to afford exclusively syn product (()-
4a was accomplished. It was anticipated that reduction
of styrene (()-21 would result in a mixture of syn and
anti products (()-4a and (()-5a that would be amenable
to separation by chromatography. Interestingly, how-
ever, 1H NMR examination of the product of this
reaction indicated the absence of the anti epimer. X-ray
analysis of hydrochloride salt crystals of compound (()-
1
pated and H NMR studies of the crude product indi-
cated that the reduction had produced an approximately
1
97:3 ratio of anti/syn isomers. The H NMR spectra of
(()-4a and (()-5a are dissimilar in the spectral region
that corresponds to aliphatic protons. The benzylic
protons (of C-2a and C-5) of (()-4a appear in the
spectrum as two distinct groups of peaks at approxi-
mately 2.9 and 3.2 ppm, whereas the corresponding
protons of (()-5a are found as a multiplet at ap-
proximately 3.4 ppm. There are also significant splitting

5-HT2A/ 2C Receptor Ligands
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16 3529
Sch em e 3
Sch em e 4
Sch em e 5
pattern and frequency differences for the methylene
protons (of C-3 and C-4) of the two products. A sample
of (()-5a was then brominated using bromine in metha-
nol to afford anti product (()-5b. The anti geometries
of compounds (()-5a and (()-5b were ultimately con-
firmed by X-ray analysis of a crystal of the tosylate salt
of (()-5b.
phospholipase C pathway by quantification of IP3 ac-
cumulation. The receptor affinity results (Table 1) show
that the three brominated compounds, (()-4b, (()-5b,
and (()-6b, possess nanomolar affinity for the receptor.
The analogues lacking the bromine, (()-4a , (()-5a , and
(()-6a , had significantly lower affinity for the 5-HT2A
receptor. Direct comparison of brominated and non-
brominated counterparts (e.g., (()-4b vs (()-4a , (()-5b
vs (()-5a , and (()-6b vs (()-6a ) shows that the presence
of a bromine atom on the phenyl ring results in a 33- to
Discu ssion
Compounds (()-4 - (()-6 were assayed for their ability
to bind to the 5-HT2A receptor and to activate the

3530 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16
Chambers et al.
Ta ble 1. Results of Radioligand Competition Binding Studies
Ta ble 2. Results of IP3 Accumulation Studies at Cloned Rat
at Cloned Receptors
5-HT2A Receptors
Ki (SEM), nM
EC50 (SEM)
% max
compd
at 5-HT2A, nM
5-HT stimulation (SEM)
5-HT2A
5-HT2C
5-HT1A
compd
(()-[125I]-DOI (()-[125I]-DOI [3H]-8-OH-DPAT
(()-syn-Br-3
(()-4a
2090(125)
nda
63(3.0)
nda
(()-syn-Br-3
(()-4a
(()-4b
(()-5a
(()-5b
(()-6a
(()-6b
DOB
16(1.5)
4.0(0.2)
59(0.6)
2.8(0.2)
34(4.7)
4.9(0.6)
11(1.2)
1.1(0.2)
2.8(0.7)a
ndb
960(48)
3000(460)
520(67)
1000(336)
550(81)
860(170)
105(6)
(()-4b
1100(283)
49(8.0)
700(130)
8.7(0.2)
310(34)
9.3(0.2)
200(9.2)
2.6(0.2)
2.2(0.3)a
25(4.7)
(()-5a
nda
nda
(()-5b
340(65)
>10000
120(14)
72(3.6)
2300(290)
2600(360)
9.8(3.7)
37(8.0)
10 @ 10 µM
33(2.0)
79(6.0)
46(2.4)
92(6.3)
22(2.6)
(()-6a
(()-6b
DOB
psilocin
mescaline
LSD
ndb
psilocin
LSD
ndb
3.5(0.62)
5.5(0.31)
1.1(0.01)
a
nd ) not determined.
Data from Chambers et al.3 nd ) not determined.
a
b
Ta ble 3. Results of Drug Discrimination Studies in LSD- or
DOI-Trained Rats
81-fold increase in affinity for members of this series.
A general requirement for potent hallucinogenic aryl-
alkylamines is that the substituent at the para position,
the 8-position of the currently discussed series, be a
bulky, hydrophobic group.21-23 If one assumes that these
new analogues are binding to the receptor in the same
general orientation as the simpler phenethylamine
congeners such as 1 or 2, then the disparity in affinity
between brominated and non-brominated compounds in
this series is not surprising. Indeed, one could use the
fact that the bromine dramatically enhances affinity to
argue that these new rigid analogues are binding in the
same region of the receptor as the prototype flexible
phenethylamines.
LSD-trained
DOI-trained
ED50
,
ED50
,
compd
µmol/kg
95% CI
µmol/kg
95% CI
(()-6ba
DOB
PSb (25-67%)
PSb (43-75%)
1.06
(0.82-1.36)
0.091
(0.0049-0.017)
a
6b was tested at doses from 1 to 6 µmol/kg (0.36-2.2 mg/kg).
PS ) partial substitution.
b
aromatic compound (()-6b is likewise very similar in
molecular shape to the respective syn and anti (()-4b
and (()-5b. This latter observation suggests that the
increase in binding affinity that results from aromati-
zation of the dihydrofuran ring may be largely of an
electronic or hydrophobic nature.
The benzofuran-containing compounds (()-6a and
(()-6b exhibited significantly higher affinity for the
5-HT2A receptor than their corresponding nonaroma-
tized counterparts. Again, this result was not surprising
in light of our previous findings that extension of the
core aromatic system to the dihydrofuran rings of
compounds containing the tetrahydrobenzo[1,2-b;4,5-b′]-
difuran nucleus enhances affinity and efficacy at this
receptor.2,3 Although it is not clear how this effect
occurs, oxidation of the dihydrofuran ring increases the
aromatic surface area of the drug, perhaps aiding
lipophilic partitioning into, and enhancement of hydro-
phobic interactions within, the agonist binding site.
Finally, a comparison of 5-HT2A receptor affinity
shows that there is little difference between the pair of
syn and the pair of anti compounds. These results
indicate no appreciable difference between the bromi-
nated syn product (()-4b compared to anti product (()-
5b and only about a 2-fold difference between the non-
brominated syn (()-4a and anti (()-5a ; it appears that
both syn and anti compounds may be accommodated
about equally well within the binding site. This similar-
ity may be explained by the observation that the syn
and anti compounds differ only slightly in their respec-
tive three-dimensional molecular structure. Comparison
of syn (()-4b and anti (()-5b illustrates the apparently
minor difference between them (Figure 1). Further,
when these structures are docked into a recently
developed homology model of the 5-HT2A receptor,24 the
bulk of the reduced carbocyclic ring projects toward the
extracellular surface of the receptor into a region that
would appear to have considerable bulk tolerance. Thus,
the difference with respect to binding to the agonist site
of the 5-HT2A receptor could also be construed as being
minor and may explain their similar pharmacology. The
Compounds (()-4b, (()-5b, (()-6a , and (()-6b were
tested for their ability to activate the phospholipase C
pathway by quantification of IP3 accumulation. These
data (Table 2) indicate that the compounds tested are
only partial agonists in this functional assay. The most
potent of the new compounds, (()-6b, while possessing
a submicromolar EC50, also was only a weak partial
agonist. The brominated compounds of the novel present
series, (()-4b, (()-5b, and (()-6b, however, displayed
at least 2-fold increased functional potency compared
to the previously synthesized syn brominated (()-3. It
is apparent that the addition of the bromine substituent
also increases functional potency, another attribute that
parallels results seen in more flexible compounds such
as 1 and 2. In some cases, this effect is very robust,
where the EC50 values of (()-6a and (()-6b differ by
about 100-fold. Once again, this finding could be inter-
preted to mean that these new analogues are binding
in the same region of the receptor as the more flexible
prototype compounds.
Finally, we selected the compound that was found to
be the most potent during in vitro analysis ((()-6b) for
behavioral tests in the two-lever drug discrimination
assay in rats trained to discriminate either saline from
LSD or saline from the hallucinogenic amphetamine
DOI (Table 3). Compound (()-6b in this paradigm
displayed, however, only partial substitution at the
highest dose tested. Despite its high affinity for the
5HT2A receptor, (()-6b did not engender LSD-like
responding. Although in DOI-trained rats 6b elicited
75% drug lever selection at the highest dose tested (6
µmol/kg), our criterion for full substitution is >80% drug
lever selection. The lack of LSD-like in vivo activity is
not related to pharmacokinetic factors because rats did

5-HT2A/ 2C Receptor Ligands
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16 3531
This mixture was stirred and cooled to 0 °C followed by
dropwise addition over 2 h of methyl 4-bromocrotonate (170
g, 951 mmol) in anhydrous acetone (1.5 L). The reaction
mixture was allowed to warm to room temperature and was
stirred for 18 h. Et2O (500 mL) was added, and the mixture
was then vacuum-filtered. The filter cake was washed well
with acetone (500 mL), and the filtrate was evaporated. The
resulting residue was dissolved in Et2O (700 mL) and washed
with cold, aqueous 2 N NaOH (2 × 200 mL). The organic layer
was washed with brine (200 mL), dried (MgSO4), filtered, and
evaporated to leave a light-yellow oil that solidified upon
cooling. This solid was recrystallized from Et2O to afford large,
emit behavioral responses (25-43% drug lever selection)
even at the lowest dose tested (1 µmol/kg). We have
previously reported on a series of mescaline analogues
in which LSD-like activity appeared to depend on
intrinsic activity in the PLC signaling pathway.25 With
an intrinsic activity of only 33% that of serotonin, (()-
6b may simply fail to provide sufficient activation of the
receptor. The partial agonist character of 4b, 5b, and
6b was also evident when 1-10 µM concentrations were
incubated with the 5-HT2A cells in the presence of 10
µM 5-HT and the IP3 response was inhibited from 25%
to 35% (data not shown). The lack of in vivo LSD-like
activity thus indicates that the novel compounds re-
ported here would not possess hallucinogenic activity
in man.
1
tan crystals (229 g, 76%): mp 48-49 °C; H NMR (300 MHz,
CDCl3) δ 3.73 (s, 3 H, ArOCH3), 3.74 (s, 3 H, CO2CH3), 4.66
(q, 2 H, ArOCH2, J ) 2.1 Hz), 6.27 (dt, 1 H, ArOCH2CHCH,
J
) 15.6, 2.1 Hz), 6.77 (m, 2 H, ArH), 7.02 (dt, 1 H,
ArOCH2CHCH, J ) 15.9, 3.6 Hz), 7.09 (m, 1 H, ArH); MS (CI)
m/z 301 (M + H), Anal. (C12H13BrO4) C, H.
We are presently investigating several new areas as
a result of these findings. First, although rigid analogue
design can be very imprecise, on the basis of the effect
of the bromine atom substitution in the present series,
we hypothesize that the compounds are binding in the
relevant region of the receptor. The lack of LSD-like
activity leads to at least three hypotheses: (1) that the
tethering bulk cannot be tolerated by the receptor, (2)
that the “side chain” is not fixed into an appropriate
dihedral angle for helical movement in the receptor that
would lead to activation, and (3) that the side chain may
require more conformational freedom for receptor acti-
vation to occur. The argument against the last hypoth-
esis, however, is that LSD, a very rigid molecule, is
active. We are currently pursuing the second explana-
tion, with the construction of additional constrained
analogues.
(()-Meth yl 2-(2,3-Dih yd r o-5-m eth oxyben zofu r a n -3-yl)-
a ceta te ((()-11). To a stirred solution of compound 10 (32.8
g, 109 mmol) in anhydrous benzene (1140 mL) at reflux was
added portionwise AIBN (1.6 g, 10 mmol). To this mixture was
added Bu3SnH (32.3 mL, 120 mmol) dissolved in anhydrous
benzene (420 mL) dropwise over a period of 1.5 h. The reaction
mixture was maintained at reflux for an additional 1 h and
was then cooled to room temperature. The solvent was
removed by rotary evaporation, the resulting residue was
dissolved in Et2O (1.0 L), and an aqueous solution of potassium
fluoride (60% w/v, 150 mL) was added. This mixture was
stirred vigorously overnight. The precipitate that formed was
removed by vacuum filtration, and the filter cake was washed
well with Et2O (500 mL). The filtrate was evaporated and
subjected to flash chromatography (4:1 hexanes/EtOAc). Frac-
tions containing the product were pooled and the solvent was
removed by rotary evaporation to leave a clear oil (24 g, 98%):
1H NMR (500 MHz, CDCl3) δ 2.54 (dd, 1 H, CH2CO2CH3, J )
16.8, 9.0 Hz), 2.74 (dd, 1 H, CH2CO2CH3, J ) 16.8, 5.7 Hz),
3.68 (s, 3 H, CO2CH3), 3.71 (s, 3 H, ArOCH3), 3.80 (m, 1 H,
ArCH, J ) 2.7 Hz), 4.18 (dd, 1 H, ArOCH2, J ) 9.0 Hz), 4.68
(t, 1 H, ArOCH2, J ) 9.0 Hz), 6.68 (m, 3 H, ArH); MS (CI) m/z
223 (M + H). Anal. (C12H14O4) C, H.
(()-(2,3-Dih ydr o-5-m eth oxyben zofu r an -3-yl)acetic Acid
(()-12). A solution of H2O (100 mL), EtOH (50 mL), and KOH
(20.0 g, 357 mmol) was added to a solution of methyl ester
(()-11 (11.9 g, 53.6 mmol) in EtOH (100 mL). This mixture
was heated at reflux for 1 h and then cooled to room
temperature. The solvents were removed by rotary evapora-
tion, and the resulting residue was dissolved in H2O (50 mL)
and acidified with cold, concentrated HCl. This solution was
then extracted with CH2Cl2 (4 × 40 mL), and the organic layers
were pooled and washed with brine, dried (MgSO4), filtered,
and evaporated to leave a white solid. The product was
recrystallized from EtOAc to yield white, granular crystals (9.8
g, 88%): mp 110-112 °C; 1H NMR (300 MHz, DMSO-d6) δ
2.54 (dd, 1 H, CH2CO2H, J ) 14.0, 9.5 Hz), 2.82 (dd, 1 H, CH2-
CO2H, J ) 14.3, 5.6 Hz), 3.72 (s, 3 H, ArOCH3), 3.75 (m, 1 H,
ArCH, J ) 6.5 Hz), 4.17 (dd, 1 H, ArOCH2, J ) 8.8, 7.1 Hz),
4.69 (t, 1 H, ArOCH2, J ) 8.9 Hz), 6.67 (s, 2 H, ArH), 6.91 (s,
1 H, ArH), 12.40 (bs, 1 H, CO2H); MS (CI) m/z 209 (M + H).
Anal. (C11H12O4) C, H.
Exp er im en ta l Section
Ch em istr y. All reagents were commercially available and
were used without further purification unless otherwise
indicated. Anhydrous THF was obtained by distillation from
benzophenone-sodium under nitrogen immediately before use.
Melting points were determined using a Thomas-Hoover
apparatus and are uncorrected. 1H NMR spectra were recorded
using either a 500 MHz Varian DRX-5000s or a 300 MHz
Bruker ARX-300 NMR spectrometer. Chemical shifts are
reported in δ values (ppm) relative to an internal reference
(0.03%, v/v) of tetramethylsilane (TMS) in CDCl3, except where
noted. Chemical ionization mass spectra (CIMS), using isobu-
tane as the carrier gas, were obtained with a Finnigan 4000
spectrometer. Elemental analyses were performed by the
Purdue University Microanalysis Laboratory and are within
(0.4% of the calculated values unless otherwise noted. Thin-
layer chromatography was performed using J . T. Baker flex
silica gel IB2-F, plastic-backed sheets with fluorescent indica-
tor, visualizing with UV light at 254 nm and with the product
eluting with 4:1 hexanes/ethyl acetate unless otherwise noted.
Column chromatography was carried out using silica gel 60,
230-400 mesh (J . T. Baker). All reactions were carried out
under an inert atmosphere of argon unless otherwise indicated.
2-Br om o-4-m eth oxyp h en ol (8).7 Bromine (285 g, 1.78
mol) was added dropwise to a stirred solution of 4-methox-
yphenol (7) (200 g, 1.61 mol) in MeOH (840 mL) at 0 °C. The
mixture was allowed to warm to room temperature and stirred
overnight. The solvent was removed by rotary evaporation and
the residue was purified by vacuum distillation (130 °C at 25
mmHg) to afford a clear liquid (262 g, 80%); 1H NMR (300
MHz, CDCl3) δ 3.72 (s, 3 H, OCH3), 5.18 (bs, 1 H, OH), 6.78
(dd, 1 H, ArH, J ) 8.9, 3.0 Hz), 6.92 (d, 1 H, ArH, J ) 8.9 Hz),
7.00 (d, 1 H, ArH, J ) 3.0 Hz); MS (CI) m/z 203 (M + H).
Met h yl 4-(2-Br om o-4-m et h oxyp h en oxy)b u t -2-en oa t e
(10). To a mechanically stirred solution of 8 (193 g, 950 mmol)
in anhydrous acetone (1.0 L) was added potassium carbonate
(131 g, 950 mmol) and potassium iodide (159 g, 958 mmol).
(()-1-Dia zo-3-(2,3-d ih yd r o-5-m eth oxyben zofu r a n -3-yl)-
p r op a n -2-on e ((()-13).4 To a solution of acid (()-12 (5.0 g,
24.0 mmol) in anhydrous benzene (40 mL) was added DMF (2
drops) followed by the dropwise addition of oxalyl chloride (2.72
mL, 31.2 mmol). After the mixture was stirred for 3 h, the
solvent and excess oxalyl chloride were removed by rotary
evaporation. Meanwhile, an Et2O solution of CH2N2 cooled in
an ice/salt bath was generated using an Aldrich Diazald Kit
and a Diazald (16.47 g, 76.9 mmol) solution in Et2O (105 mL)
dripped into a 60 °C solution of KOH (5.25 g, 94 mmol) in
Carbitol (32 mL) and H2O (11 mL). The solid acyl chloride of
(()-12 was dissolved in anhydrous Et2O (55 mL) and added
dropwise to the CH2N2 solution. After the mixture was stirred
at 0 °C for 1.5 h, a precipitate formed and the excess CH2N2

3532 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16
Chambers et al.
was removed by attaching the apparatus to a water aspirator.
After most of the solvent had been removed, the remaining
volatiles were removed by rotary evaporation to leave the
diazoketone as a yellow solid (5.4 g, 97%). An analytical sample
of the diazoketone was recrystallized from Et2O: mp 70-72
°C (lit.4 mp 73-74 °C); 1H NMR (300 MHz, CDCl3) δ 2.74 (m,
2 H, CH2COCHN2), 3.74 (s, 3 H, ArOCH3), 3.90 (m, 1 H, ArCH),
4.19 (dd, 1 H, ArOCH2, J ) 9.1, 6.0 Hz), 4.70 (t, 1 H, ArOCH2,
J ) 9.0 Hz), 5.25 (s, 1 H, CH2COCHN2), 6.73 (m, 3 H, ArH);
MS (CI) m/z 233 (M + H).
(()-Meth yl 3-(2,3-Dih yd r o-5-m eth oxyben zofu r a n -3-yl)-
p r op ion a te ((()-14). To a stirred solution of diazoketone (()-
13 (5.4 g, 23.3 mmol) in anhydrous MeOH (100 mL) was added
very slowly a solution of silver benzoate (0.4 g, 1.7 mmol) in
anhydrous Et3N (4.0 mL). This reaction mixture was stirred
overnight and was then diluted with Et2O (100 mL) and
vacuum-filtered to remove the solids. The filter cake was
washed well with Et2O, and the filtrate was concentrated. The
residue was dissolved in CH2Cl2 (200 mL), washed with aque-
ous 0.5 M NaOH (2 × 40 mL) and brine (20 mL), dried
(MgSO4), filtered, and evaporated to leave a tan oil (5.2 g,
95%): 1H NMR (500 MHz, CDCl3) δ 1.93 (m, 1 H, ArCHCH2-
CH2), 2.08 (m, 1 H, ArCHCH2CH2), 2.38 (m, 2 H, ArCHCH2-
CH2), 3.42 (m, 1 H, ArCH), 3.67 (s, 3 H, CO2CH3), 3.77 (s, 3 H,
ArOCH3), 4.19 (dd, 1 H, ArCHCH2O, J ) 8.8, 5.8 Hz), 4.59 (t,
1 H, ArCHCH2O, J ) 8.8 Hz), 6.68 (m, 2 H, ArH), 6.75 (s, 1 H,
ArH); MS (CI) m/z 237 (M + H). Anal. (C13H16O4) C, H.
addition of saturated Na2CO3 solution (500 mL). The layers
were separated, and the aqueous phase was extracted with
CH2Cl2 (3 × 350 mL). The organic phases were pooled and
washed with saturated Na2CO3 (200 mL), dried (MgSO4),
filtered, and evaporated to leave a white solid that was
recrystallized from EtOAc to afford white crystals (117 g,
83%): mp 88-89 °C; 1H NMR (500 MHz, CDCl3) δ 1.96 (m, 1
H, ArCHCH2CH2), 2.08 (m, 1 H, ArCHCH2CH2), 2.46 (s, 3 H,
ArCH3), 3.50 (m, 1 H, ArCH), 3.75 (s, 3 H, ArOCH3), 4.12 (m,
3 H, ArCHCH2CH2, ArCHCH2O), 4.52 (t, 1 H, ArCHCH2O, J
) 9.0 Hz), 6.67 (m, 3 H, ArH), 7.36 (d, 2 H, ArH, J ) 9.0 Hz),
7.81 (d, 2 H, ArH, J ) 6.0 Hz); MS (CI) m/z 349 (M + H). Anal.
(C18H20O5S) C, H.
Con tin u a tion of Alter n a tive Rou te. (()-3-(5-Meth oxy-
2,3-d ih yd r oben zofu r a n -3-yl)p r op ion itr ile ((()-18). Potas-
sium cyanide (16.0 g, 246 mmol) was added to a solution of
tosylate (()-17 (58.8 g, 169 mmol) in absolute EtOH (1.0 L).
The mixture was heated at reflux for 9 h and then cooled to
room temperature. The solids were removed by vacuum
filtration, and the filter cake was washed well with EtOH. The
filtrate volume was reduced under vacuum (ca. 400 mL) and
was then diluted with Et2O (500 mL). This solution was then
washed with H2O (500 mL) and brine (200 mL), dried (MgSO4),
filtered, and evaporated to leave a tan oil that was homoge-
neous by TLC (33 g, 97%). An analytical sample was purified
by column chromatography (4:1 hexanes/EtOAc). 1H NMR (500
MHz, CDCl3) δ 1.98 (m, 1 H, ArCHCH2CH2), 2.07 (m, 1 H,
ArCHCH2CH2), 2.41 (m, 2 H, ArCHCH2CH2), 3.55 (m, 1 H,
ArCH), 3.77 (s, 3 H, ArOCH3), 4.25 (m, 1 H, ArCHCH2O), 4.63
(dt, 1 H, ArCHCH2O, J ) 8.9, 2.6 Hz), 6.72 (m, 3 H, ArH); MS
(CI) m/z 204 (M + H). Anal. (C12H13NO2) C, H, N.
Con tin u a tion of Alter n a tive Rou te. (()-3-(5-Meth oxy-
2,3-d ih yd r oben zofu r a n -3-yl)p r op ion ic Acid ((()-15). Ni-
trile (()-18 (36.5 g, 180 mmol) was dissolved in EtOH (1.0 L),
and then 2 N NaOH (500 mL) was added. The reaction mixture
was heated at reflux overnight and then cooled to room
temperature. The EtOH was removed by rotary evaporation,
and the resulting suspension was cooled and acidified by
dropwise addition of 2 N HCl. The mixture was extracted with
CH2Cl2 (4 × 400 mL). The organic layers were pooled and
washed with brine (300 mL), dried (Na2SO4), filtered, and
evaporated to leave a white solid. Recrystallization from EtOAc
gave off-white needles (33 g, 83%). NMR spectral data and the
melting point were identical to those reported above.
(()-3-(2,3-Dih yd r o-5-m et h oxyb en zofu r a n -3-yl)p r op i-
on ic Acid ((()-15). Methyl ester (()-14 (5.2 g, 22.0 mmol)
was dissolved in EtOH (80 mL), a solution of KOH (5.0 g, 89.0
mmol) in H2O (25 mL) and EtOH (13 mL) was added, and the
mixture was stirred overnight. The EtOH was removed by
rotary evaporation, and the resulting mixture was diluted with
H2O (50 mL) and acidified with cold, concentrated HCl. The
resulting suspension was extracted with CH2Cl2 (4 × 40 mL),
and the organic layers were pooled, washed with brine (50 mL),
dried (MgSO4), filtered, and evaporated to leave a white,
amorphous solid. This solid was recrystallized from Et2O to
1
afford white crystals (4.6 g, 94%): mp 100-101 °C; H NMR
(500 MHz, CDCl3) δ 1.77 (m, 1 H, ArCHCH2CH2), 2.00 (m, 1
H, ArCHCH2CH2), 2.34 (m, 2 H, ArCHCH2CH2), 3.48 (m, 1 H,
ArCH), 3.73 (s, 3 H, ArOCH3), 4.22 (dd, 1 H, ArCHCH2O, J )
8.7, 6.0 Hz), 4.59 (t, 1 H, ArCHCH2O, J ) 9.5 Hz), 6.72 (m, 2
H, ArH), 6.91 (s, 1 H, ArH), 12.21 (bs, 1 H, CO2H); MS (CI)
m/z 223 (M + H). Anal. (C12H14O4) C, H.
(()-6-Meth oxy-2,2a,3,4-tetr ah ydr on aph th o[1,8-bc]fu r an -
5-on e ((()-19). Propionic acid (()-15 (33.0 g, 150 mmol) was
dissolved in anhydrous benzene (850 mL), and then DMF (4
mL) was added. Oxalyl chloride (26 mL, 298 mmol) was added
dropwise to the mixture, and the reaction mixture was stirred
at room temperature for 4 h. The solvent and excess oxalyl
chloride were removed by rotary evaporation, and the residue
was dissolved in CH2Cl2 (460 mL). The reaction flask was
submerged in an ice bath, and then anhydrous SnCl4 (22 mL,
188 mmol) was added dropwise. The ice bath was removed,
and the reaction mixture was stirred for 1 h and then poured
onto ice (ca. 300 g). The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 250 mL). The
organic layers were then pooled and washed with brine (200
mL), dried (MgSO4), filtered, and evaporated to leave a tan
solid that was recrystallized from EtOAc (29.7 g, 97%): mp
105-106 °C; 1H NMR (500 MHz, CDCl3) δ 1.89 (dq, 1 H,
ArCHCH2CH2, J ) 7.0, 2.0 Hz), 2.31 (m, 1 H, ArCHCH2CH2),
2.57 (m, 1 H, ArCHCH2CH2), 2.76 (m, 1 H, ArCHCH2CH2),
3.68 (m, 1 H, ArCH), 3.88 (s, 3 H, ArOCH3), 4.10 (dd, 1 H,
ArCHCH2O, J ) 6.4, 4.5 Hz), 4.84 (t, 1 H, ArCHCH2O, J )
8.5 Hz), 6.69 (d, 1 H, ArH, J ) 3.6 Hz), 6.93 (d, 1 H, ArH, J )
3.6 Hz); MS (CI) m/z 205 (M + H). Anal. (C12H12O3) C, H.
Alter n a tive Rou te to P r op ion ic Acid (()-15. (()-2-(5-
Meth oxy-2,3-d ih yd r oben zofu r a n -3-yl)eth a n ol ((()-16). To
a stirred suspension of lithium aluminum hydride (32.0 g, 840
mmol) in anhydrous Et2O (500 mL) was added dropwise an
anhydrous Et2O (450 mL) solution of methyl ester (()-11 (45.5
g, 205 mmol). The reaction mixture was stirred at room
temperature overnight and quenched by the careful dropwise
addition of a solution of H2O (25 mL) in THF (250 mL) followed
by 5 N KOH (20 mL). The solids were removed by vacuum
filtration through a pad of Celite, and the filter cake was
washed well with warm THF (500 mL). The solvents were then
removed by rotary evaporation to leave a clear oil that was
homogeneous by TLC analysis (39.0 g, 89%). An analytical
sample was purified by column chromatography (1:1 hexanes/
EtOAc as eluent): 1H NMR (500 MHz, CDCl3) δ 1.61 (bs, 1 H,
CH2OH), 1.84 (m, 1 H, ArCHCH2CH2), 2.04 (m, 1 H, ArCHCH2-
CH2), 3.56 (m, 1 H, ArCH), 3.75 (t, 2 H, ArCHCH2CH2, J )
4.2 Hz), 3.76 (s, 3 H, ArOCH3), 4.25 (dd, 1 H, ArCHCH2O, J )
8.9, 6.5 Hz), 4.65 (t, 1 H, ArCHCH2O, J ) 8.9 Hz), 6.68 (m, 2
H, ArH), 6.77 (m, 1 H, ArH); MS (CI) m/z 195 (M + H), 177
(M + H - H2O). Anal. (C11H14O3) C, H.
Con tin u a tion of Alter n a tive Rou te. (()-2-(5-Meth oxy-
2,3-dih ydr oben zofu r an -3-yl)eth yl p-Tolu en esu lfon ate ((()-
17). A solution of Et3N (170 mL, 1.22 mol) in CH2Cl2 (400 mL)
was added dropwise to a 0 °C solution of alcohol (()-16 (78.6
g, 405 mmol) and p-toluenesulfonyl chloride (163 g, 855 mmol)
in CH2Cl2 (1300 mL). After being stirred for 1 h, the reaction
mixture was allowed to warm to room temperature and stirred
an additional 2 h. The reaction was then quenched by the
(()-5-Am in om eth yl-6-m eth oxy-2a ,3,4,5-tetr a h yd r o-2H-
n a p h th o[1,8-bc]fu r a n -5-ol Hyd r och lor id e ((()-20). Zinc
iodide (0.4 g, 1.3 mmol) was added to a solution of ketone (()-
19 (10.0 g, 49 mmol) in CH2Cl2 (500 mL). TMSCN (7.2 mL, 54
mmol) was then added, and the reaction mixture was heated
at reflux for 14 h. Comparison of the IR spectrum of the
reaction mixture to the IR spectrum of the starting material

5-HT2A/ 2C Receptor Ligands
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16 3533
(()-19 indicated the absence of the CdO peak at 1681 cm-1
and the appearance of a new peak at 2361 cm-1 (CN). The
reaction mixture was then concentrated by rotary evaporation,
and the remaining residue was dissolved in anhydrous THF
(200 mL) and added dropwise to a suspension of LiAlH4 (2.8
g, 74 mmol) in anhydrous Et2O (100 mL). The reaction mixture
was stirred overnight, and then the reaction was quenched
by the careful addition of H2O (10 mL) dissolved in THF (100
mL). The resulting suspension was then filtered, and the filter
cake was washed well with warm THF (500 mL). The filtrate
was then diluted with Et2O (300 mL) and washed with H2O
(2 × 200 mL), dried (Na2SO4), filtered, and evaporated to leave
a tan solid. This solid was dissolved in anhydrous Et2O (200
mL) and acidified with anhydrous 1 N HCl in EtOH. The
solvents were then removed by rotary evaporation and the
resulting white solid was recrystallized from EtOH to afford
and evaporated to leave a clear oil. The resulting oil was
dissolved in anhydrous Et2O, filtered through a small plug of
glass wool, and acidified with 1 N ethanolic HCl. The precipi-
tate was collected by vacuum filtration and then recrystallized
from i-PrOH to yield needle-like crystals (1.5 g, 88%): mp
258-260 °C (dec); 1H NMR (500 MHz, D2O) δ 1.38 (q, 1 H,
ArCHC(3)H2CH2, J ) 12.2 Hz), 1.84 (m, 1 H, ArCHC(3)H2-
CH2), 2.04 (m, 2 H, ArCHCH2C(4)H2), 2.92 (dt, 1 H, ArCHCH2N,
J ) 10.2, 3.6 Hz), 3.18 (d, 2 H, CH2N, J ) 8.8 Hz), 3.32 (m, 1
H, ArCHCH2O), 3.78 (s, 3 H, ArOCH3), 4.01 (dd, 1 H,
ArCHCH2O, J ) 12.7, 8.7 Hz), 4.84 (t, 1 H, ArCHCH2O, J )
8.3 Hz), 6.89 (s, 1 H, ArH); MS (CI) m/z 298 (M + H), 300.
Anal. (C13H17BrClNO2) C, H, N.
(()-syn -N -T r iflu o r o a c e t y l-1-(8-b r o m o -6-m e t h o x y -
2a ,3,4,5-t et r a h yd r o-2H -n a p h t h o[1,8-bc]fu r a n -5-yl)a m i-
n om et h a n e ((()-22). To a stirred suspension of the hy-
drobromide salt of (()-4b (1.3 g, 3.6 mmol) and 4-N,N-
(dimethylamino)pyridine (0.04 g, 0.3 mmol) in CH2Cl2 (40 mL)
was added Et3N (16.0 mL, 12.0 mmol), and the mixture was
cooled to 0 °C. Trifluoroacetic anhydride (2.5 mL, 17 mmol)
was then added to the reaction dropwise. The mixture was
allowed to warm to room temperature and stirred for 8 h. The
mixture was then diluted with CH2Cl2 (50 mL) and washed
with 2 N HCl (50 mL), saturated NaHCO3 (50 mL), and brine
(50 mL). The organic phase was then dried (MgSO4), filtered,
and evaporated to leave a white solid that was recrystallized
from Et2O (1.2 g, 92%): mp 197-198 °C; 1H NMR (500 MHz,
CDCl3) δ 1.55 (q, 1 H, ArCHC(3)H2CH2, J ) 11.4 Hz), 1.86
(dt, 1 H, ArCHC(3)H2CH2, J ) 13.1, 5.8 Hz), 2.02 (d, 2 H,
ArCHCH2C(4)H2, J ) 11.6 Hz), 3.16 (q, 1 H, ArCHCH2N, J )
6.3 Hz), 3.38 (m, 1 H, ArCHCH2N), 3.42 (m, 1 H, ArCHCH2N),
3.53 (p, 1 H, ArCHCH2O, J ) 6.7 Hz), 3.81 (s, 3 H, ArOCH3),
4.06 (dd, 1 H, ArCHCH2O, J ) 13.0, 8.3 Hz), 4.81 (t, 1 H,
ArCHCH2O, J ) 8.2 Hz), 6.72 (s, 1 H, ArH), 7.26 (bs, 1 H,
NHCOCF3); MS (CI) m/z 394 (M + H), 396. Anal. (C15H15BrF3-
NO3) C, H, N.
(()-N-Tr iflu or oa cetyl-1-(8-br om o-6-m eth oxy-4,5-d ih y-
d r o-3H-n a p h t h o[1,8-bc]fu r a n -5-yl)a m in om et h a n e ((()-
23). A solution of DDQ (1.73 g, 7.6 mmol) in dioxane (250 mL)
was added slowly to a solution of (()-22 (3.0 g, 7.6 mmol) in
dioxane (100 mL). The reaction mixture was stirred at room
temperature for 8 h and was then diluted with CH2Cl2 (100
mL) and filtered through a short pad of silica gel. The silica
gel was washed thoroughly with CH2Cl2, and the filtrate and
wash were then reduced to dryness by rotary evaporation. The
black solid that resulted was subjected to column chromatog-
raphy (1:1 hexanes/EtOAc as eluent), resulting in an off-white,
solid product that was recrystallized from Et2O to afford white,
fluffy crystals (2.3 g, 78%): mp 172-174 °C; 1H NMR (500
MHz, CDCl3) δ 1.92 (m, 1 H, ArCCH2CH2), 2.13 (dt, 1 H,
ArCCH2CH2, J ) 6.2 Hz), 2.72 (m, 1 H, ArCCH2CH2), 2.85
(dt, 1 H, ArCCH2CH2, J ) 13.9, 2.2 Hz), 3.34 (td, 1 H,
ArCHCH2N, J ) 13.6, 3.1 Hz), 3.49 (m, 1 H, ArCHCH2N), 3.64
(dt, 1 H, ArCH, J ) 12.3, 3.5 Hz), 3.91 (s, 3 H, ArOCH3), 7.03
(s, 1 H, ArH), 7.40 (s, 1 H, ArH), 7.62 (bs, 1 H, NHCOCF3);
MS (CI) m/z 392 (M + H). Anal. (C15H13BrF3NO3) C, H, N.
(()-(8-Br om o-6-m eth oxy-4,5-d ih yd r o-3H-n a p h th o[1,8-
bc]fu r a n -5-yl)a m in om eth a n e Hyd r och lor id e ((()-6b). A
solution of (()-23 (1.1 g, 2.8 mmol) in MeOH (150 mL) was
cooled to 0 °C, and then 5 N KOH solution (25 mL) was added
slowly. The reaction mixture was allowed to warm to room
temperature and stirred overnight, and then the MeOH was
removed by rotary evaporation. The residue was diluted with
H2O (25 mL) and extracted with Et2O (4 × 100 mL), dried (Na2-
SO4), filtered, and evaporated to afford a clear oil. This oil was
dissolved in Et2O (100 mL), filtered through a plug of glass
wool, and neutralized by the slow addition of 1 N ethanolic
HCl. The solvents were removed by rotary evaporation and
the resulting white residue was recrystallized from MeOH to
afford the title compound (0.6 g, 67%): mp 222-223 °C; 1H
NMR (500 MHz, CD3OD) δ 1.82 (m, 1 H, ArCCH2CH2), 2.19
(dt, 1 H, ArCCH2CH2, J ) 11.6, 2.7 Hz), 2.72 (t, 1 H, ArCCH2-
CH2, J ) 13.4 Hz), 2.75 (m, 1 H, ArCCH2CH2), 3.04 (dd, 1 H,
ArCHCH2N, J ) 13.1, 6.4 Hz), 3.10 (dd, 1 H, ArCHCH2N, J )
1
white crystals (11.5 g, 87%): mp 191-193 °C (dec); H NMR
(500 MHz, DMSO-d6) δ 1.56 (q, 1 H, ArCHCH2CH2, J ) 12.4
Hz), 1.78 (t, 1 H, ArCHCH2CH2, J ) 13.2 Hz), 1.96 (m, 1 H,
ArCHCH2CH2, J ) 5.2 Hz), 2.31 (d, 1 H, ArCHCH2CH2, J )
13.0 Hz), 2.86 (d, 1 H, CH2N, J ) 12.9 Hz), 3.24 (d, 1 H, CH2N,
J
) 13.1 Hz), 3.26 (m, 1 H, ArCH, obscured in DMSO
spectrum, present in D2O spectrum), 3.73 (s, 3 H, ArOCH3),
3.86 (dd, 1 H, ArCHCH2O, J ) 12.1, 4.3 Hz), 4.67 (t, 1 H,
ArCHCH2O, 8.3 Hz), 6.68 (dd, 2 H, ArH, 9.1, 8.5 Hz), 7.89 (bs,
2 H, CH2NH2); MS (CI) m/z 236 (M + H), 218 (M + H - H2O).
(()-(6-Meth oxy-2a ,3-d ih yd r o-2H-n a p h th o[1,8-bc]fu r a n -
5-yl)a m in om eth a n e Hyd r och lor id e ((()-21). Concentrated
HCl (40 mL) was added to a solution of the hydrochloride salt
of amino alcohol (()-20 (18 g, 67 mmol) in absolute EtOH (500
mL). The solution was heated at reflux for 6 h, at which time it
had taken on a green color. The reaction mixture was concen-
trated to dryness, and the resulting white solid was recrystal-
lized from EtOH to afford white crystals (12 g, 71%): mp 255-
257 °C (dec); 1H NMR (500 MHz, D2O) δ 1.98 (t, 1 H, Ar-
CHCH2CH, J ) 12.3 Hz), 2.48 (dt, 1 H, ArCHCH2CH, J ) 16.5,
7.5 Hz), 3.44 (m, 1 H, ArCHCH2O), 3.69 (s, 3 H, ArOCH3), 3.75
(d, 1 H, CH2N, J ) 13.2 Hz), 4.04 (d, 1 H, CH2N, J ) 13.0 Hz),
4.06 (m, 1 H, ArCHCH2O), 4.77 (t, 1 H, ArCHCH2O, J ) 8.7
Hz), 6.04 (d, 1 H, ArCCHCH2, J ) 4.2 Hz), 6.62 (d, 1 H, ArH,
J ) 5.7 Hz), 6.70 (d, 1 H, ArH, J ) 9.0 Hz); MS (CI) m/z 218
(M + H), 201 (M + H - NH3). Anal. (C13H16ClNO2) C, H, N.
(()-syn -(6-Met h oxy-2a ,3,4,5-t et r a h yd r o-2H -n a p h t h o-
[1,8-bc]fu r a n -5-yl)a m in om et h a n e Hyd r och lor id e ((()-
4a ). The hydrochloride salt of aminostyrene (()-21 (7.0 g, 28
mmol) was dissolved in a mixture of MeOH (175 mL) and
EtOH (50 mL) and added to a Parr hydrogenation flask
containing 10% Pd/C (0.70 g) and EtOH (10 mL). The flask
was placed on a hydrogenation apparatus, pressurized to 60
psi of H2, and shaken for 24 h. The reaction mixture was then
vacuum-filtered through a pad of Celite, and the filter cake
was washed well with MeOH. The solvents were removed by
rotary evaporation, and the resulting white solid was recrys-
tallized from EtOH (7.0 g, 99%): mp 262-263 °C; 1H NMR
(500 MHz, D2O) δ 1.34 (q, 1 H, ArCHC(3)H2CH2, J ) 12.3 Hz),
1.87 (dt, 1 H, ArCHC(3)H2CH2, J ) 11.7, 5.5 Hz), 2.00 (t, 2 H,
ArCHCH2C(4)H2, J ) 14.6 Hz), 2.90 (dd, 1 H, ArCHCH2N, J
) 12.6, 4.2 Hz), 3.17 (dd, 1 H, CH2N, J ) 12.6, 4.8 Hz), 3.22
(m, 2 H, CH2N, ArCHCH2O), 3.75 (s, 3 H, ArOCH3), 3.91 (dd,
1 H, ArCHCH2O, 12.8, 8.2 Hz), 4.71 (t, 1 H, ArCHCH2O, J )
8.2 Hz, obscured in D2O spectrum, present in DMSO spec-
trum), 6.64 (d, 1 H, ArH, J ) 8.5 Hz), 6.70 (d, 1 H, ArH, J )
8.5 Hz); MS (CI) m/z 220 (M + H), 203 (M + H - NH3). Anal.
(C13H18ClNO2) C, H, N.
(()-syn -(8-Br om o-6-m et h oxy-2a ,3,4,5-t et r a h yd r o-2H -
n a p h t h o[1,8-bc]fu r a n -5-yl)a m in om et h a n e H yd r och lo-
r id e ((()-4b). Bromine (0.80 g, 5.0 mmol, 0.2 N MeOH
solution) was added dropwise to a solution of (()-4a (1.28 g,
5.0 mmol) in MeOH (150 mL) at 0 °C. The yellow solution
turned clear upon warming to room temperature. Et2O (200
mL) was added, and the precipitate that formed was collected
by vacuum filtration. This solid was stirred in concentrated
NH4OH solution (300 mL) and extracted with CH2Cl2 (4 × 100
mL). The organic phases were pooled, dried (Na 2SO4), filtered,

3534 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16
Chambers et al.
12.9, 6.4 Hz), 3.45 (m, 1 H, ArCHCH2N), 3.83 (s, 3 H, ArOCH3),
7.07 (s, 1 H, ArH), 7.48 (s, 1 H, ArH); MS (CI) m/z 296 (M +
H). Anal. (C13H15BrClNO2) C, H, N.
evaporation to leave a clear oil. This oil was dissolved in
anhydrous Et2O (100 mL) and filtered through a small plug
of glass wool. The solution was then acidified with ethanolic 1
N HCl and the precipitate that formed was collected by
vacuum filtration and then recrystallized from i-PrOH to afford
(()-syn -N-Tr iflu or oa cetyl-(6-m eth oxy-2a ,3,4,5-tetr a h y-
d r o-2H-n a p h t h o[1,8-bc]fu r a n -5-yl)a m in om et h a n e ((()-
24). To a stirred suspension of the hydrochloride salt of (()-
4a (3.1 g, 12.1 mmol) and 4-N,N-(dimethylamino)pyridine (0.12
g, 0.98 mmol) in CH2Cl2 (150 mL) was added Et3N (6.0 mL,
43.0 mmol), and the mixture was cooled to 0 °C. Trifluoroacetic
anhydride (4.13 mL, 29.0 mmol) was then added to the reaction
mixture dropwise. The reaction mixture was then allowed to
warm to room temperature and stirred for 8 h. The mixture
was diluted with CH2Cl2 (200 mL) and washed with 2 N HCl
(100 mL), saturated NaHCO3 (100 mL), and brine (100 mL).
The organic phase was then dried (MgSO4), filtered, and
evaporated to leave a white solid that was recrystallized from
Et2O (3.5 g, 91%): mp 181-183 °C; 1H NMR (500 MHz, CDCl3)
δ 1.51 (q, 1 H, ArCHC(3)H2CH2, J ) 13.0 Hz), 1.88 (dt, 1 H,
ArCHC(3)H2CH2, J ) 9.6, 5.7 Hz), 2.01 (m, 2 H, ArCHCH2C-
(4)H2), 3.23 (p, 1 H, ArCHCH2N, J ) 7.0 Hz), 3.28 (m, 1 H,
ArCHCH2O), 3.40 (m, 1 H, ArCHCH2N), 3.57 (p, 1 H,
ArCHCH2N, J ) 6.3 Hz), 3.82 (s, 3 H, ArOCH3), 3.96 (dd, 1 H,
ArCHCH2O, J ) 12.9, 8.2 Hz), 4.72 (t, 1 H, ArCHCH2O, J )
8.1 Hz), 6.62 (s, 2 H, ArH), 7.64 (bs, 1 H, NHCOCF3); MS (CI)
m/z 316 (M + H). Anal. (C15H16F3NO3) C, H, N.
(()-N-Tr iflu or oacetyl-(6-m eth oxy-4,5-dih ydr o-3H-n aph -
th o[1,8-bc]fu r a n -5-yl)a m in om eth a n e ((()-25). A solution
of DDQ (2.16 g, 9.5 mmol) in dioxane (330 mL) was added
slowly to a solution of (()-24 (3.0 g, 9.5 mmol) in dioxane (125
mL). The reaction mixture was stirred at room temperature
for 8 h and was then diluted with CH2Cl2 (100 mL) and filtered
through a short pad of silica gel. The silica gel was washed
well with CH2Cl2, and the filtrate and wash were reduced to
dryness by rotary evaporation. The dark solid that resulted
was subjected to column chromatography (1:1 hexanes/EtOAc
as eluent), resulting in a off-white, solid product that was
recrystallized from Et2O to afford white, fluffy crystals (2.6 g,
88%): mp 141-142 °C; 1H NMR (500 MHz, CDCl3) δ 1.95 (m,
1 H, ArCCH2CH2), 2.13 (dt, 1 H, ArCCH2CH2, J ) 13.9, 2.2
Hz), 2.73 (t, 1 H, ArCCH2, J ) 13.6 Hz), 2.85 (d, 1 H, ArCCH2,
J ) 16.2 Hz), 3.37 (dt, 1 H, ArCHCH2N, J ) 12.3, 3.5 Hz),
3.52 (m, 1 H, ArCHCH2N), 3.68 (m, 1 H, ArCHCH2N), 3.92 (s,
3 H, ArOCH3), 6.88 (d, 1 H, ArH, J ) 8.8 Hz), 7.28 (d, 1 H,
ArH, J ) 8.8 Hz), 7.35 (s, 1 H, ArH), 7.83 (bs, 1 H, NHCOCF3);
MS (CI) m/z 314 (M + H). Anal. (C15H14F3NO3) C, H, N.
1
needle-like crystals (0.14 g, 81%): mp 185-186 °C; H NMR
(500 MHz, D2O) δ 1.22 (q, 1 H, ArCHC(3)H2CH2, J ) 11.2 Hz),
1.52 (q, 1 H, ArCHC(3)H2CH2, J ) 9.7 Hz), 2.18 (dd, 1 H,
ArCHCH2C(4)H2, J ) 12.5, 3.3 Hz), 2.30 (d, 1 H, ArCHCH2C-
(4)H2, J ) 12.2 Hz), 3.30 (dd, 2 H, CH2N, J ) 12.4, 7.6 Hz),
3.34 (m, 1 H, ArCHCH2O), 3.38 (m, 1 H, ArCHCH2N), 3.78 (s,
3 H, ArOCH3), 3.97 (t, 1 H, ArCHCH2O, J ) 10.4 Hz), 4.84 (t,
1 H, ArCHCH2O, J ) 8.4 Hz), 6.71 (d, 1 H, ArH, J ) 8.3 Hz),
6.77 (d, 1 H, ArH, J ) 8.5 Hz); MS (CI) m/z 220 (M + H), 203
(M + H - NH3). Anal. (C13H18ClNO2) C, H, N.
(()-a n ti-(8-Br om o-6-m et h oxy-2a ,3,4,5-t et r a h yd r o-2H-
n a p h t h o[1,8-bc]fu r a n -5-yl)a m in om et h a n e H yd r och lo-
r id e ((()-5b). Bromine (0.16 g, 1.0 mmol, 0.2 N MeOH
solution) was added dropwise to a solution of the hydrochloride
salt of (()-5a (0.26 g, 1.0 mmol) in MeOH (25 mL) at 0 °C.
The reaction mixture was stirred and allowed to warm to room
temperature overnight. Et2O (75 mL) was added, and the
precipitate that formed was collected by vacuum filtration.
This solid was stirred in concentrated NH4OH solution (100
mL) and extracted with Et2O (4 × 100 mL). The organic phases
were pooled and dried (Na2SO4), filtered, and evaporated to
leave a clear oil. This oil was dissolved in anhydrous Et2O,
filtered through a small plug of glass wool, and acidified with
1 N ethanolic HCl. The precipitate was collected by vacuum
filtration and then recrystallized from i-PrOH to yield needle-
like crystals (0.26 g, 78%): mp 231-232 °C; 1H NMR (500
MHz, CD3OD) δ 1.25 (1 H, q, ArCHC(3)H2CH2, J ) 12.1 Hz),
1.53 (1 H, m, ArCHC(3)H2CH2), 2.18 (1 H, dd, ArCHCH2C(4)-
H2, J ) 12.3, 3.8 Hz), 2.25 (1 H, m, ArCHCH2C(4)H2), 3.16 (1
H, m, CH2N), 3.37 (1 H, m, CH2N), 3.43 (1 H, m, ArCHCH2N),
3.76 (3 H, s, ArOCH3), 3.96 (1 H, t, ArCHCH2O, J ) 8.8 Hz),
4.75 (1 H, t, ArCHCH2O, J ) 7.9 Hz), 6.80 (1 H, s, ArH); MS
(CI) m/z 298 (M + H). Anal. (C13H17BrClNO2) C, H, N.
P h a r m a cology Meth od s: Cell Cu ltu r e. Cells stably
transfected to express the rat 5-HT2A, rat 5-HT2C, or human
5-HT1A receptor were maintained in Dulbecco’s minimum
essential medium, containing 10% dialyzed fetal bovine serum
(Gibco BRL) and supplemented with L-glutamine, Pen/Strep,
and Geneticin.26 The cells were cultured at 37 °C in a H2O
saturated atmosphere of 95% air and 5% CO2. For radioligand
binding assays, cells were split into 100 mm culture dishes
when they reached 90% confluency. Upon reaching 100%
confluency in the culture dishes, the cells were washed with
sterile filtered phosphate-buffered solution and left to incubate
in serum-free Opti-MEM for 5 h. After incubation, the cells
were harvested by centrifugation (15000g, 20 min) and placed
immediately in a freezer at -80 °C until the assay was
performed. For IP3 accumulation experiments, the cells were
seeded into 24-well plates and assays were performed when
70% confluency was achieved.
Ra d ior ecep tor Com p etition Assa ys. For saturation as-
says, 0.125-5.0 nM [125I]-DOI was used for the 5-HT2A and
5-HT2C receptors and 0.25-10 nM [3H]-8-OH-DPAT was used
for the 5-HT1A receptor. The total volume of the assay was 250
µL. Nonspecific binding was defined in the presence of 10 µM
cinanserin (rat 5-HT2A receptor expressing cells), 10 µM
mianserin (rat 5-HT2C receptor expressing cells), or 10 µM
5-HT (human 5-HT1A receptor expressing cells). Competition
binding experiments were carried out in a total volume of 500
µL with 0.20 nM [125I]-DOI or 2.0 nM [3H]-8-OH-DPAT.
Previously harvested cells were resuspended and added to each
well containing assay buffer (50 mM Tris, 0.1 mM EDTA, 10
mM MgCl2; pH 7.4), radioligand, and test compound (or in the
case of the saturation assays, cinanserin, mianserin, or 5-HT).
Incubation was carried out at 25 °C for 60 min and terminated
by rapid filtration using a prechilled Packard 96-well harvester
with GF/B Uni-filters that had been preincubated for 30 min
in 0.3% polyethylenimine. The filters were rinsed using chilled
wash buffer (10 mM Tris, 154 mM NaCl) and left to dry
(()-(6-Meth oxy-4,5-d ih yd r o-3H-n a p h th o[1,8-bc]fu r a n -
5-yl)a m in om eth a n e Hem ioxa la te ((()-6a ). A solution of
(()-25 (1.7 g, 5.4 mmol) in MeOH (250 mL) was cooled to 0
°C, and then 5 N KOH solution (30 mL) was added slowly.
The reaction mixture was allowed to warm to room temper-
ature and stirred overnight, and then the MeOH was removed
by rotary evaporation. The residue was diluted with H2O (25
mL) and extracted with Et2O (4 × 100 mL), dried (Na2SO4),
filtered, and evaporated to afford a clear oil. This oil was
dissolved in Et2O (100 mL), filtered through a plug of glass
wool, and neutralized by the slow addition of oxalic acid (54
mL, 0.1 M in MeOH). The solvents were removed, and the
resulting white residue was recrystallized from MeOH to afford
1
the hemioxalate salt (0.9 g, 59%): mp 243 °C; H NMR (500
MHz, CD3OD) δ 1.82 (m, 1 H, ArCCH2CH2), 2.17 (dt, 1 H,
ArCCH2CH2, J ) 11.9, 2.8 Hz), 2.69 (t, 1 H, ArCCH2, J ) 13.6
Hz), 2.78 (dt, 1 H, ArCCH2, J ) 12.0, 3.1 Hz), 3.03 (m, 2 H,
ArCHCH2N, J ) 13.0, 6.4 Hz), 3.46 (m, 1 H, ArCHCH2), 3.81
(s, 3 H, ArOCH3), 6.88 (d, 1 H, ArH, J ) 8.7 Hz), 7.19 (d, 1 H,
ArH, J ) 8.7 Hz), 7.35 (s, 1 H, ArH); MS (CI) m/z 218 (M +
H). Anal. (C15H17NO6) C, H, N.
(()-a n ti-(6-Met h oxy-2a ,3,4,5-t et r a h yd r o-2H-n a p h t h o-
[1,8-bc]fu r a n -5-yl)a m in om et h a n e Hyd r och lor id e ((()-
5a ). The primary amine of (()-6a (0.17 g, 0.83 mmol) was
dissolved in hexane (200 mL) and added to a Parr flask
containing 10% Pd/C (0.10 g) and hexane (5 mL). The flask
was then pressurized and shaken at 65 psi of H2 for 24 h. The
solution was filtered through Celite, the filter cake was washed
well with EtOH, and the solvents were removed by rotary

5-HT2A/ 2C Receptor Ligands
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16 3535
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overnight. The following day, Microscint-O was added and
radioactivity was determined using a TopCount (Packard)
scintillation counter. GraphPad Prism (GraphPad Software,
San Diego, CA) was used to analyze the saturation and
competition binding curves.
In ositol Tr ip h osp h a te Accu m u la tion Stu d ies in Cells
Exp r essin g th e 5-HT2A Recep tor . Accumulation of inositol
phosphates was determined using a modified version of a
previously published protocol.27 Briefly, cells expressing the
rat 5-HT2A receptor were labeled for 18-20 h in CRML
medium containing 1.0 µCi/mL [3H]-myo-inositol. After pre-
treatment of the cells with 10 µM pargyline/10 mM LiCl for
15 min, the cells were exposed to a test drug for 30 min at 37
°C under an atmosphere of 95% O2 and 5% CO2. The assay
was terminated by aspirating the medium and adding 10 mM
formic acid. Following incubation for 16 h at 4 °C, the [3H]-
inositol phosphates were separated from the cellular debris
on Dowex-1 ion-exchange columns and eluted with 1.0 M
ammonium formate and 0.10 M formic acid. The vials were
counted for tritium using a TriCarb scintillation counter
(Packard Instrument Corp.).
Dr u g Discr im in a tion Stu d ies. Male Sprague-Dawley
rats (Harlan Laboratories, Indianapolis, IN) weighing 200-
220 g at the beginning of the drug discrimination study were
divided into six groups (n ) 8-15 per group) and trained to
discriminate LSD tartrate or DOI hydrochloride from saline.
None of the rats had previously received drugs or behavioral
training. Water was freely available in the individual home
cages, and a rationed amount of supplemental feed (Purina
Lab Blox) was made available after experimental sessions to
maintain approximately 80% of free-feeding weight.
Six standard experimental chambers (model E10-10RF,
Coulbourn Instruments, Lehigh Valley, PA) consisted of
modular test cages enclosed within sound-attenuated cubicles
with fans for ventilation and background white noise. A white
house light was centered near the top of the front panel of the
cage, which was also equipped with two response levers sep-
arated by a food hopper, all positioned 2.5 cm above the floor.
A fixed ratio (FR) 50 schedule of food reinforcement (Noyes
45 mg of dustless pellets) in a two-lever paradigm was used.
The complete drug discrimination procedure has been de-
scribed in detail elsewhere.28
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Ack n ow led gm en t. We thank Stewart Frescas and
Amjad Qandil for their helpful contributions and dis-
cussions pertaining to this work. We also thank for their
kind donations Dr. David J ulius (UCSF) for the 5-HT2A
and 5-HT2C cell lines as well as Dr. Christopher Harber
(Pharmacia) for the 5-HT1A cell line. This work was
supported by Grant DA02189 from NIDA and by a grant
from the Heffter Research Institute.
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