Geometry-affinity relationships of the selective serotonin receptor ligand 9-(aminomethyl)-9,10-dihydroanthracene

Article abstract of DOI:10.1021/jm010354g

With the exception of its two aromatic rings and basic nitrogen atom, 9-(aminomethyl)-9,10-dihydroanthracene (AMDA; 1) is remarkably devoid of the pharmacophore features usually associated with high-affinity receptor ligands such as the heteroatom hydrogen bonding features of the endogenous ligand serotonin. AMDA does contain a phenylethylamine skeleton within a tricyclic ring system, and the presence of the second aromatic group is necessary for optimal receptor affinity. The structural requirements for the binding of AMDA at 5-HT_2A receptors were investigated with respect to the geometric relationship between the two aromatic rings. It appears that the geometry of the AMDA parent is in the optimal range for fold angle between aromatic moieties. Evaluation of conformationally constrained derivatives of AMDA suggests that a chain extended trans, gauche form is most likely responsible for high affinity.

Full text of DOI:10.1021/jm010354g

1656
J . Med. Chem. 2002, 45, 1656-1664
Geom etr y-Affin ity Rela tion sh ip s of th e Selective Ser oton in Recep tor Liga n d
9-(Am in om eth yl)-9,10-d ih yd r oa n th r a cen e
Scott P. Runyon,† Srinivas Peddi,† J ason E. Savage,‡ Bryan L. Roth,‡ Richard A. Glennon,† and
Richard B. Westkaemper*,†
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, and
Departments of Biochemistry and Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and
the NIMH Psychoactive Drug Screening Program
Received J uly 30, 2001
With the exception of its two aromatic rings and basic nitrogen atom, 9-(aminomethyl)-9,10-
dihydroanthracene (AMDA; 1) is remarkably devoid of the pharmacophore features usually
associated with high-affinity receptor ligands such as the heteroatom hydrogen bonding features
of the endogenous ligand serotonin. AMDA does contain a phenylethylamine skeleton within
a tricyclic ring system, and the presence of the second aromatic group is necessary for optimal
receptor affinity. The structural requirements for the binding of AMDA at 5-HT2A receptors
were investigated with respect to the geometric relationship between the two aromatic rings.
It appears that the geometry of the AMDA parent is in the optimal range for fold angle between
aromatic moieties. Evaluation of conformationally constrained derivatives of AMDA suggests
that a chain extended trans, gauche form is most likely responsible for high affinity.
In tr od u ction
The serotonin (5-hydroxytryptamine; 5-HT) receptor
family consists of a large number (>14) of distinct
entities that have been identified using cloning technol-
ogy. Many therapeutically useful drugs have 5-HT
receptors as their targets.1,2 Specifically, 5-hydroxy-
tryptamine2 (5-HT2) receptors have been implicated
as the site of action for hallucinogens, atypical anti-
psychotic drugs, and certain atypical antidepressants.1,2
For these reasons, generation of structurally novel
agents that interact with 5-HT2 receptors is of consider-
able current interest.3 Typically, simple unsubstituted
phenylethylamines show very low affinity for 5-HT2
receptors (e.g., phenylethylamine, 5-HT2A Ki > 10 000
nM).4 Some time ago, examination of receptor models
suggested that the affinity of structures containing a
phenylethylamine skeleton could be enhanced by intro-
ducing a second aromatic moiety, perhaps by participat-
ing in additional aromatic-aromatic interactions be-
tween ligand and receptor.5 This prompted us to prepare
and evaluate 9-(aminomethyl)-9,10-dihydroanthracene
(AMDA, 1, Figure 1) which has proven to be a unique
5-HT2 selective antagonist that most likely binds to the
receptor in a fashion different from that of structurally
related, nonselective tricyclic antidepressants.4,6,7 In
fact, AMDA fails to conform7 to existing pharmacophore
models for 5-HT2A antagonists.8,9 Because of its remark-
F igu r e 1. Structures and receptor affinities of compounds
1-10 at [3H]ketanserin-labeled cloned 5-HT2A sites. Values
represent the mean of computer-derived Ki estimates (using
LIGAND) of quadruplicate determinations. Standard errors
typically range between 15 and 25% of the Ki value. The Ki
values for compounds 1-3 (ref 4) and 8 (ref 6) were previously
reported.
ably simple structure and impressive selectivity,7 we
explored a series of AMDA analogues to determine the
importance of the tricyclic ring system, the effects of
* Correspondence: Richard B. Westkaemper, Department of
Medicinal Chemistry, P.O. Box 980540, School of Pharmacy,
Virginia Commonwealth University, Richmond VA 23298-0540.
E-mail: richard.westkaemper@vcu.edu. Telephone: 804-828-6449.
Fax: 804-828-7625.
altering the tricyclic aromatic ring fold angle, and the
consequences of restricting conformational freedom of
the ligand ammonium ion on 5-HT2 receptor affinity.
† Virginia Commonwealth University.
‡ Case Western Reserve University School of Medicine and the
NIMH Psychoactive Drug Screening Program.
10.1021/jm010354g CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/15/2002

Geometry-Affinity Relationships of AMDA
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1657
Sch em e 1a
a
Reagents and conditions: (a) trimethylsilyl cyanide, ZnI2,
CH2Cl2; (b) LiAlH4, THF; (c) Eaton’s reagent RT.
Compound 16 was prepared through catalytic hydro-
genation of 9,10-dihydro-9,10-ethanoanthracene-11-one
oxime13 using 10% Pd/charcoal. Synthesis of compound
19 (Scheme 2) was initially attempted through the
conversion of 1 to the N-formyl derivative 28 with the
hope of subsequent cyclization to the dihydroisoquino-
line 31. This route proved unsuccessful under several
cyclization conditions. Compound 19 was successfully
prepared using the method reported by Grunewald et
al. (Scheme 2).17 Compound 1 was converted into the
carbamate 29 using methyl chloroformate followed by
cyclization to the amide 30 with POCl3 and SnCl4. The
resulting amide 30 was reduced to the amine 19 using
BH3 in THF. Compound 18 was prepared from 9-acetyl-
9,10-dihdroanthracene18 via the reductive amination
procedure of Barney et al.19
F igu r e 2. Structures and receptor affinities of compounds 1
and 11-19 at 5-HT2A represent the mean of computer-derived
Ki estimates (using LIGAND) of quadruplicate determinations
at [3H]ketanserin-labeled cloned 5-HT2A sites. Standard errors
typically range between 15 and 25% of the Ki value.
Ch em istr y
All target compounds (1-19) are shown in Figures 1
and 2. Compounds 3, 4, and 13 are commercially
available; compound 4 was purchased as a free base and
subsequently converted to its HCl salt10 using ethereal
HCl and anhydrous ether. Compounds 1,4 2,4 6,11 7,5
8,6 10,12 and 17,13 were prepared as previously reported.
The preparation of phenylalkyamine 5 was initiated
with a BH3 reduction of commercially available 2-(ben-
zyl)benzoic acid followed by PCC oxidation to provide
2-(benzyl)benzaldehyde in good overall yield. A Henry
reaction was then employed to generate 2-(2-benzyl-
phenyl)-trans-nitroethene from 2-(benzyl)benzaldehyde
and nitromethane. Reduction of the nitrostyrene was
accomplished using AlH4 in THF to provide the target
amine 5. Compounds 9, 11, and 12 were all prepared
in an analogous manner starting from the reported
carboxylic acids (23-25).14-16 The desired amides were
prepared from the respective acid chlorides via the
addition of anhydrous ammonia in THF. The target
amines 9, 11, and 12 were obtained in good yield
following reduction of the amides using either BH3 or
LiAlH4 in THF. The preparation of compound 14 began
(Scheme 1) with the formation 2-(benzyl)benzoyl chlo-
ride from 2-(benzyl)benzoic acid and SOCl2 in benzene;
2-(benzyl)benzoyl chloride was then treated with CH3-
MgCl in THF to provide 2-(benzyl)acetophenone (26)
in moderate yield. The conversion of 2-(benzyl)aceto-
phenone (26) to 3-amino-2-(2-benzylphenyl)-2-propanol
(27) was accomplished using trimethylsilyl cyanide
and ZnI2 followed by LiAlH4 reduction. This product
was cyclodehydrated to 9-methyl-9-aminomethyl-9,10-
dihydroanthracene oxalate (14) using Eaton’s reagent.
Resu lts a n d Discu ssion
With the exception of its two aromatic rings and basic
nitrogen atom, AMDA is remarkably devoid of the
pharmacophore features usually associated with high-
affinity receptor ligands such as the heteroatom hydro-
gen bonding features of the endogenous ligand seroto-
nin. AMDA (1, Figure 1) contains a phenylethylamine
skeleton within a tricyclic ring system. The structural
requirements for the binding of AMDA (1) at 5-HT2A
receptors were investigated with respect to the necessity
of, and relationship between, the two aromatic rings as
well as the effects of altering the aminoalkyl side chain
conformation by molecular dissection and elaboration
of conformationally constrained derivatives.
Na tu r e of th e Tr icyclic Rin g System . Removing
one aromatic ring from AMDA (1; Ki ) 20 nM) drasti-
cally reduces affinity as indicated by the tetrahydro-
naphthalene 2 (Ki > 10 000 nM). This suggests that the
enhanced affinity of AMDA (1) over phenylethylamine
(3; Ki ) 16 800 nM) is not due solely to the presence of
the central ring. The simple presence of two aromatic
rings is also not sufficient for optimal affinity as
demonstrated by compounds 4-10. The 2,2-diphenyl-
ethylamine 4 (Ki ) 4610 nM), while enhanced in affinity
compared to phenylethylamine (3), has 240-fold lower
affinity than AMDA (1). Similarly, 2-(2-benzylphenyl)-
ethylamine (5; Ki ) 1810 nM) has a 9-fold greater
affinity than phenylethylamine (3) but has a 90-fold
lower affinity than AMDA (1). Thus, it appears that the
high affinity of AMDA (1) could be attributable to its

1658 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8
Runyon et al.
Sch em e 2a
a
Reagents and conditions: (a) methyl chloroformate, triethyl amine, CH2Cl2; (b) POCl3, reflux 24 h, SnCl4, 6 h; (c) BH3-THF reflux;
(d) formic acid, acetic anhydride; (e) POCl3; (f) PPA; (g) TiCl4.
Ta ble 1. Geometric Parameters and 5-HT2A Receptor Affinities
R
T1
Ar-N N-plane
T2
Ki
compd (deg)a (deg)b
(Å)c
(Å)d
(deg)e
(nM)f
12
11
17
16
13
8
19
14
18
1
15
10
6
7
4
111
118
120
121
121
123
137
142
144
147
155
164
174
131
0.6
2.4
0
5.3
5.3
4.7
5.1
5.9
5.2
5.2
5.1
5.2
5.2
5.1
4.8
5.1
5.2
5.3
0.6
0.2
1.3
1.3
1.3
1.3
-0.6
1.8
1.6
1.6
2.0
1.8
1.7
1.2
0.3
172
173
122
177
137
174
170
178
173
177
169
123
169
176
175
6780
770
>10000
>10000
9530
4130
296
0.7
1.3
2.0
1.7
3.7
0.9
1.8
2.2
0
65
193
20
330
2300
4490
112
F igu r e 3. Rotational conformers on AMDA (1) and phenyl-
ethylamine (3).
0
31
88
pounds with a substantial symmetrical aromatic fold
can bind to the receptor with high affinity (Figure 1,
Table 1).
4610
Con for m a tion a l P r op er ties of AMDA a n d Re-
la ted Tr icyclic Com p ou n d s. Unsubstituted dihydro-
anthracene adopts a symmetrical folded structure with
9- and 10-position hydrogens in either a pseudoaxial or
pseudoequatorial configuration.20 Structural informa-
tion from crystallographic,21 1H NMR,22 and molecular
mechanics based conformational analysis23 indicates
that 9-position substituents of 9,10-dihydroanthracene
derivatives preferably adopt the pseudoaxial configu-
ration (Figure 3). Molecular mechanics based confor-
mational analysis of the 9,10-dihydroanthracene AMDA
performed by ourselves and of 10-aminomethyl-9,10-
dihydro-1,2-dihydroxyanthracene24 in vacuo also sug-
gest the dihydroaromatic system is most likely folded
with the aminoalkyl substituent in the pseudoaxial
position. The aminomethyl substituent is capable of
adopting a trans, gauche (exo) or a gauche, gauche
(endo) conformation of nearly equal energies calculated
for either the free base or the protonated amine using
molecular mechanics. The apparent slight stability of
the endo conformer (6.8 kcal/mol; two 1,4 interactions)
compared to the exo form (8.0 kcal/mol; one 1,4 inter-
action) is somewhat unexpected, even though the
same behavior was observed with 10-aminomethyl-9,10-
dihydro-1,2-dihydroxyanthracene.24 Since molecular me-
chanics energy minimizations tend to overemphasize
van der Waals interactions when performed in vacuo,
often producing artificially compact, folded structures,
the conformational analysis using molecular mechanics
a
b
Fold angle R as defined by Rabideau (ref 20). Twist angle
C1-C2-C4-C5. c Distance between aromatic ring centroid and
d
amine nitrogen. Distance between aromatic ring plane and amine
nitrogen. e Side chain torsion angle C2-C3-C5-N. f [3H]Ketanserin
radioligand with cloned 5-HT2A receptors.
tricyclic configuration. However, incorporation of two
aromatic rings fused to a central cyclopentane ring
produces a compound (6; Ki ) 4490 nM) that has very
low 5-HT2A affinity. The [a,d]dibenz-fused cycloheptane
7 (Ki ) 112 nM) has a lower affinity than AMDA (1)
but binds reasonably well. The [a,d]dibenz-fused cyclo-
heptene 8 (Ki ) 4130 nM) is reduced in affinity by 37-
fold compared to the saturated cycloheptane 7. The
position of the fused aromatic ring is important; the
[a,d]dibenz-fused cyclohexane AMDA (1) has 36-fold
higher affinity than the [a,c]dibenz-fused cyclohexane
9 (Ki ) 710 nM). The fully aromatic derivative of AMDA,
anthracene 10 (Ki ) 2300 nM), has 100-fold lower
affinity than the dihydro derivative AMDA (1). Consid-
eration of the binding data in Figure 1 and Table 1
invites a simple conclusion: Compounds with a nearly
coplanar (6, 10) or orthogonal (4) orientation of the two
necessary aromatic rings have low affinity while com-

Geometry-Affinity Relationships of AMDA
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1659
in the presence of explicit water and by using semi-
empirical molecular orbital methods (AM1, ∆E ) 2.4
kcal/mol; MNDO, ∆E ) 1.2 kcal/mol) in vacuo were also
conducted. In all cases, the endo and exo forms again
have similar calculated energies, with the endo form
having slightly lower energy, providing further support
for conformational flexibility of the aminomethyl sub-
stituent of AMDA and the existence of both exo and
endo minima. While it is not known which, or if both,
rotomers of AMDA contribute to 5-HT2A binding, the
CNS activity of arylethylamines is usually attributed
to the trans form.25 Thus, AMDA has a significant
symmetrical aromatic fold with relatively free rotation
about the aminomethyl-dihydroanthracene bond pro-
ducing both exo and endo minima (Figure 3). As
previously noted, compounds with less than optimal
affinity at 5-HT2A receptors have either a nearly planar
(6, 10), folded but twisted (7), or orthogonal arrange-
ment (4) of two aromatic rings (Figure 1). The relation-
ship between biological activity and the nature of a
folded tricyclic aromatic ring system has also been noted
for tricyclic antipsychotics (phenothiazine and thioxan-
thene derivatives) and antidepressants (dibenzazepine
and cyclopheptadiene derivatives).26 Phenothiazines and
thioxanthenes that have a symmetrical fold of nearly
133-139° (R) and fused ring torsion angle τ1 ∼ 0° tend
to be antipsychotics (presumably D2 antagonists) while
dibenzazepine and dibenzocycloheptadienes that have
a folded aromatic configuration (R ) 125°) with a
distinct twist (τ1 ∼ 10°) tend to be antidepressants
(presumably by inhibition of neurotransmitter up-
take).26 Thus, the geometric characteristics of AMDA
and AMDA analogues are reminiscent of classical
tricyclic agents. The major difference between AMDA
and AMDA analogues and classical tricyclic agents is
simply that the former contain a phenylethylamine
skeleton while the later have a “phenylbutylamine”
skeleton.7
F igu r e 4. Superimposition of a single aromatic ring from
compounds 1 (endo conformation), 1 (exo conformation), and
the conformationally restricted AMDA analogues 16, 17, and
19.
of exo AMDA. Similarly, 9- and 10-methylation (14 and
15) produce decreased aromatic folding and introduce
steric bulk, but methylation produces compounds with
reasonable receptor affinity. It should be noted that 9-
and 10-alkylation tend to render an energetically rea-
sonable flattened-central-ring conformer as well as the
typical boat form. Taken together, the data in Table 1
suggest that there may be some optimum aromatic fold
angle near the value for AMDA in the 137-155° range.
For compounds with a nearly symmetrical fold (τ1 < 4°),
there appears to be a parabolic relationship between
receptor affinity and the fold angle R (for compounds 1,
6, 8, 10-15, 18, and 19, y ) yo + ax + bx2, r2 ) 0.65;
this list excludes the “twisted” compounds 4, 7 and
compounds 16, 17 (which do not have finite Ki values)).
Since the AMDA parent is the highest affinity member
in the series, it is not yet known whether AMDA has
the optimal aromatic ring fold. There is no quantitative
relationship (linear or parabolic) between affinity and
any of the other geometric parameters listed in Table 1
(r2 < 0.3) and, in most cases, the range of values is
small. It is rather remarkable that affinity appears to
be sensitive to relatively small changes in aromatic fold
angle.
Va r ia tion of th e Ar om a tic F old An gle (Un r e-
str icted Am in om eth yl Rota tion ). Since AMDA has
a significantly folded aromatic tricyclic system with free
rotation about the aminomethyl bond, we synthesized
and evaluated several AMDA derivatives with varying
fold angles R (R as defined by Rabideau23) while
maintaining a rotatable alkylamine (Figure 2, Table 1).
In this series, the fold angle R falls between a maximum
of 174° and a minimum of 111°. Some of the compounds
in Table 1 have multiple ring conformations; the geo-
metric parameters listed in Table 1 are for the most
energetically stable and most exo AMDA-like conformer.
Introduction of the ethano (11; Ki ) 770 nM) and
methano (12; Ki ) 6780 nM) bridges effectively de-
creases the fold angle (Table 1) but also introduces steric
bulk. Since the ethano bridge is tolerated, and 11 has
higher affinity than the methano-bridged compound 12,
it is not likely that steric effects are overwhelming. In
addition, 9-mono- (14) and 10,10-dimethylated (15)
compounds bind with reasonable affinity (Ki ) 65 and
330 nM, respectively), indicating that alkylation at the
positions of bridge attachment is sterically tolerated
(Figure 1, Table 1). Introduction of the alkyl bridge, as
in 11 and 12, also effectively “inverts” the aminomethyl
group to the pseudoequatorial position but still places
the amine in reasonable proximity to the amino group
Con for m a tion a lly Restr icted AMDA An a logu es.
Of course, the conformational disposition of all sub-
stances is not static, and AMDA most certainly exists
as a rapidly interconverting population of species. We
have synthesized and evaluated a number of conforma-
tionally restricted AMDA variants in an attempt to
delineate the “AMDA pharmacophore” (Figure 2). As
with any such study, results are complicated by the
necessity of introducing additional steric bulk to ac-
complish a decrease in rotational degrees of freedom,
as well as changing other features that may be impor-
tant (i.e., aromatic ring fold angle). The [2.2.2]bicyclo
derivatives 16 and 17 (Ki > 10,000 nM) are both
reasonable approximations of the exo and endo amino-
methyl-axial AMDA conformers, respectively (Figures
3 and 4), but have no measurable 5-HT2A affinity. Since
compound 18 (Ki ) 193 nM) does have measurable
affinity and binds with only 10-fold lower affinity than
AMDA, the R-carbon bridge should be sterically toler-
ated. It appears that, while reasonable placement of the
nitrogen can be achieved, the aromatic fold angle may
be too acute (R ∼ 120°) to be compatible with good
receptor affinity. The aromatic fold angle of compound
19 is closer to the presumed optimum, and it has
reasonably good receptor affinity (K1 ) 296 nM). The

1660 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8
Runyon et al.
suspension was warmed to room temperature and heated at
reflux (6 h). The suspension was allowed to cool, and water
(0.25 mL), 10% NaOH (0.25 mL), and Celite (1.0 g) were
cautiously added. The suspension was filtered through a
sintered glass filter, and the filtrate was dried (MgSO4) and
concentrated under reduced pressure to provide a pale yellow
oil (0.43 g). The oil was dissolved in anhydrous Et2O (55 mL),
and 2 mL of anhydrous HCl (1.0 M in Et2O) was added. The
resulting precipitate was collected by filtration, washed with
anhydrous Et2O, and recrystallized from 2-propanol to provide
5 (0.38 g, 75%) as a white powder: mp 167-168 °C (lit.29 mp
169-170 °C). 1H NMR (DMSO-d6): δ 2.85-2.96 (m, 4H, CH2),
4.02 (s, 2H, Ar-CH2-Ar), 7.15-7.30 (brm, 9H, Ar-H). 13C
NMR (DMSO-d6): δ 30.42, 38.06, 126.32, 127.06, 127.35,
128.75, 129.01, 130.01, 130.79, 136.10, 139.47, 141.03.
fused piperidine ring of 2,3,7,11b-tetrahydrodibenzo-
[d,e,h]isoquinoline (19) has two possible orientations
that place the nitrogen atom either above or below the
aromatic plane. On the basis of the geometric consid-
erations discussed above, we suspect that one of the
aminomethyl axial conformers may be responsible for
the reasonable affinity of the compound although all
conformers are accessible and will likely bind to the
receptor. It should be noted that none of the conformers
of 19 closely resemble the endo form of AMDA. Com-
pound 19 (Ki ) 296 nM) has the highest affinity of any
conformationally constrained analogue in the AMDA
class. This observation is particularly interesting given
that 9-methyl AMDA (14, Ki ) 65 nM, i.e., an equatorial
methyl is tolerated) has modest affinity as does N-
methyl AMDA7 (Ki ) 52 nM), suggesting that methyla-
tion is tolerated but decreases affinity. Compound 19
can exist in one of two conformational minima with the
aminoalkyl chain either pseudoequitorial (R ) 137°, τ1
) 1.7°, τ2 ) 170°; E )14.2 kcal/mol, as shown in Table
1) or a pseudoaxial (R ) 0°, τ1 ) 5°, τ2 ) 157°, E ) 16.8
kcal/mol). While both conformers should be energetically
accessible, the former is energetically more stable by
about 3 kcal/mol and is most likely the form bound to
the receptor. Since compound 19 more closely resembles
the exo form of 1 than the endo form, we speculate that
the exo conformer of AMDA may be the bound form. It
should be noted that while compounds 2, 9, 13, and 16-
19 are chiral, all were evaluated as their racemates.
While 2, 13, 16, and 17 do not show significant affinity,
the Ki values for 9, 18, and 19 may be underestimated
due to evaluation of the racemate.
9-Am in om eth yl-9,10-dih ydr oph en an th r en e Hydr och lo-
r id e (9). Borane-THF complex (1.0 M in THF, 7.87 mL, 7.87
mmol) was added in a dropwise manner to a stirred solution
of 9,10-dihydrophenanthrene-9-carboxamide (23, 0.35 g, 1.57
mmol) in anhydrous THF (2 mL) under N2 at 0 °C. The mixture
was slowly warmed to room temperature and then heated at
reflux (8 h). The reaction mixture was allowed to cool to room
temperature, and HCl (6.0 M, 4 mL) was added with caution.
The mixture was heated at reflux (1 h) and allowed to cool to
room temperature, and the solvent was removed under re-
duced pressure. Water (20 mL) was added, and the residue
was extracted with EtOAc (20 mL). The aqueous portion was
made basic with 10% NaOH and extracted with EtOAc (3 ×
25 mL). The combined EtOAc extracts were washed with water
and brine, dried (MgSO4), and concentrated under reduced
pressure to give 0.30 g (89%) of the amine as a colorless oil.
The oil was dissolved in anhydrous Et2O (30 mL), and HCl
(1.0 M in Et2O ≈ 1.46 mmol) was added. The precipitate was
collected by filtration, dried, and recrystallized (EtOAc/MeOH)
1
to provide 9 (0.18 g) as colorless needles: mp 263-264 °C. H
NMR (DMSO-d6): δ 2.69 (brs, 2H, CH2), 2.98-3.11 (m, 2H,
CH2), 3.33-3.37 (t, J ) 7.5 Hz, 1H, CH), 7.29-7.9 (brm, 8H,
Ar-H), 8.3 (brs, 2H, NH2). 13C NMR (DMSO-d6): δ 30.53,
36.06, 41.28, 123.90, 124.53, 127.78, 128.29, 128.46, 128.53,
128.93, 129.96, 133.79. Anal. (C15H15N‚HCl) C, H, N.
Con clu sion
AMDA is a high-affinity, 5-HT2 selective antagonist
that possesses a geometry inconsistent with previously
reported 5-HT2 antagonist pharmacophore models.8,9 On
the basis of the present studies, it is expected that
structural variations that retain a phenylethylamine
skeleton in a configuration similar to that of exo AMDA,
within a tricyclic system containing two symmetrically
folded aromatic rings (fold angle, R ) 137° - 155°),
should have high 5-HT2A affinity. On the basis of
the pharmacological properties of AMDA, compounds
in this class are expected to function as 5-HT, selective
antagonists.
1-(Am in om et h yl)d ib en zo[b,e]b icyclo[2.2.2]oct a d ien e
Hyd r och lor id e (11). Borane-THF complex (1.0 M in THF)
(15 mL, 15.0 mmol) was added under N2 at 0 °C to a stirred
solution of dibenzo[b,e]bicyclo[2.2.2]octadiene-1-carboxamide
(24, 1.0 g, 3.74 mmol) in anhydrous THF (5.0 mL). The solution
was allowed to warm to room temperature and heated at reflux
(10 h). The solution was allowed to cool, HCl (6.0 M, 10 mL)
was cautiously added, and the solution was heated at reflux
(0.5 h). The solution was allowed to cool to room temperature,
made basic with 10% NaOH (≈40 mL), and extracted with
CH2Cl2 (3 × 45 mL). The organic extracts were combined, dried
(MgSO4), and concentrated under reduced pressure to provide
a colorless oil. The oil was dissolved in anhydrous Et2O (40
mL), and ethereal HCl was added until no further precipitate
formed. The preciptitate was collected by filtration and washed
with anhydrous Et2O (10 mL) to provide a white solid. The
solid was recrystallized from 2-propanol/Et2O to provide 0.70
g (63%) of 11 as white needles: mp 310-313 °C (lit.15 mp 313-
315 °C). 1H NMR (DMSO-d6): δ 1.56-1.61 (m, 2H, CH2), 1.72-
1.75 (m, 2H, CH2), 3.97 (s, 2H, CH2-NH2), 4.44 (s, 1H, CH),
7.15-7.39 (brm, 8H, Ar-H). Anal. (C17H17N‚HCl) C, H, N.
9-Am in om eth yl-9,10-d ih yd r o-9,10-m eth a n oa n th r a cen e
Hydr och lor ide (12). A solution of 9,10-dihydro-9,10-methano-
anthracene-9-carboxamide (25, 0.50 g, 2.13 mmol) in anhy-
drous THF (3 mL) was cooled (0 °C), and borane-THF complex
(1.0 M in THF) (6.39 mL, 6.39 mmol) was added under N2.
The solution was warmed to room temperature and heated at
reflux (6 h). The solution was cooled (0 °C), HCl (6.0 M, 5 mL)
was cautiously added, and the mixture was again heated at
reflux (0.5 h). The solution was allowed to cool, made basic
(10% NaOH, ≈40 mL), and extracted with CH2Cl2 (3 × 35 mL).
The organic extracts were combined, dried (MgSO4), and
concentrated under reduced pressure to provide an opaque
semisolid. The semisolid was dissolved in anhydrous Et2O (35
Exp er im en ta l Section
Syn th esis. Melting points were determined using a Thomas-
Hoover melting point apparatus and are uncorrected. Proton
magnetic resonance (1H NMR and 13C NMR) spectra were
obtained with
a Varian Gemini 300 spectrometer, using
tetramethylsilane as an internal standard. Infrared spectra
were recorded on a Nicolet Avatar 360 E.S.P. FT-infrared
spectrometer. Elemental analysis was performed by Atlantic
Microlab, Inc., and determined values are within 0.4% of
theory. Thin-layer chromatography (TLC) was performed using
silica gel-coated GHLF plates (250 µm, 2.5 × 10 cm, Analtech,
Inc., Newark, DE). Anhydrous solvents were purchased and
stored under nitrogen over Molecular Sieves. Medium-pressure
column chromatography was carried out using silica gel 60,
0.040-0.063 mm (230-400 mesh), Lancaster Synthesis.
2-(2-Ben zylp h en yl)eth yla m in e Hyd r och lor id e (5). A
solution of 2-(2-benzylphenyl)-trans-nitroethene (22, 0.50 g,
2.09 mmol) in anhydrous THF (5 mL) was added at 0 °C under
N2 to a stirred suspension of LiAlH4 (0.15 g, 4.18 mmol) and
AlCl3 (0.31 g, 2.30 mmol) that was maintained at 0 °C. The

Geometry-Affinity Relationships of AMDA
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1661
mL), and ethereal HCl was added until no more precipitate
formed. The white suspension was filtered and the filter cake
washed with anhydrous Et2O (10 mL). The white solid was
recrystallized from MeOH/2-propanol to provide 12 (0.28 g,
filtration and washed with anhydrous acetone. The solid was
recrystallized (anhydrous acetone) to provide 16 (0.09 g) as a
white solid: mp 228-229 °C. 1H NMR (DMSO-d6): δ 1.45-
1.49 (d, J ) 12 Hz, 1H, CH), 2.13-2.21 (t, J ) 12 Hz, 1H,
CH), 3.49-3.52 (d, J ) 9 Hz, 1H, CH), 4.42 (s, 1H, CH), 4.62
(s, 1H, CH), 7.10-7.39 (brm, 8H, Ar-H). 13C NMR (DMSO-
d6): 833.46, 42.53, 46.81, 49.04, 124.00, 124.79, 126.25, 126.41,
126.62, 126.87, 127.12, 164.93. Anal. (C16H15N‚C2H2O4) C, H,
N.
1
51%) as white crystals: mp 315-318 °C dec. H NMR (CD3-
OD): δ 2.37-2.38 (d, J ) 1.5 Hz, 2H, CH2), 3.88 (s, 2H, CH2-
NH2), 4.19 (s, 1H, CH), 6.77-6.82 (brm, 4H, Ar-H), 7.02-
7.11 (brm, 4H, Ar-H). 13C NMR (CD3OD): δ 39.33, 51.45,
59.35, 69.06, 121.19, 123.61, 126.95, 127.43, 149.80, 153.17.
Anal. (C16H15N‚HCl) C, H, N.
9-(1-Am in oeth yl)-9,10-d ih yd r oa n th r a cen e Hyd r och lo-
r ide (18). Hexamethyldisilazane (2.17 g, 13.49 mmol), 9-acetyl-
9,10-dihydroanthracene18 (1.0 g, 4.49 mmol), and anhydrous
CH2Cl2 (40 mL) were placed in a flask equipped with a septum
inlet and cooled (0 °C) under N2. TiCl4 solution (1.0 M in CH2-
Cl2, 2.25 mL, 2.25 mmol) was added in a dropwise manner,
and the reaction mixture was allowed to warm to room
temperature and stirred (18 h). The reaction was carefully
quenched by the dropwise addition of NaCNBH3 (1.7 g, 27.0
mmol) in MeOH (10 mL), and the suspension was allowed to
stir for an additional 1 h. The reaction mixture was then made
basic with NaOH (5 M) to pH 13 and extracted with EtOAc (3
× 25 mL). The combined extracts were washed with water and
brine, dried (MgSO4), and concentrated under reduced pres-
sure to provide a dark brown oil. The oil was purified with
medium-pressure column chromatography using CHCl3/MeOH
(9:1) to provide (0.40 g, 40%) a colorless oil. The oil was
dissolved in anhydrous Et2O, and HCl (1.0 M in Et2O) (1.46
mL) was added. The precipitate was collected by filtration,
washed with anhydrous Et2O, and recrystallized (EtOAc/
MeOH) to provide 18 as colorless needles: mp 292-293 °C.
1H NMR (DMSO-d6): δ 1.03-1.05 (d, J ) 6 Hz, 3H, CH3),
2.99-3.06 (q, J ) 13.5 Hz, 1H, CH), 3.85-4.13 (dd, J ) 18
Hz, 2H, CH2), 4.36-4.34 (d, J ) 6 Hz, 1H, CH), 7.31-7.7.69
(m, 8H, Ar-H). 13C NMR (DMSO-d6): δ 16.45, 35.17, 49.61,
50.81, 126.54, 126.86, 127.44, 128.36, 129:24, 129.72, 135.25,
136.21, 137.36, 137.60. Anal. (C17H19N‚HCl) C, H, N.
9-Meth yl-9-a m in om eth yl-9,10-d ih yd r oa n th r a cen e Ox-
a la te (14). 3-Amino-2-(2-benzylphenyl)-2-propanol (27, 0.50
g, 2.07 mmol) was added under N2 to a stirred solution of
Eaton’s reagent (10 mL). The mixture was allowed to stir for
3 h at room temperature. The reaction was terminated by
gradual addition of water (150 mL). The solution was made
basic by addition of 10% NaOH (≈50 mL) and extracted with
CH2Cl2 (3 × 75 mL). The organic extracts were dried (MgSO4)
and concentrated under reduced pressure to provide (0.32 g,
1.43 mmol, 69%) a pale yellow oil. The oil was dissolved in
anhydrous acetone (50 mL), and anhydrous oxalic acid (0.14
g, 1.43 mmol) was added. The solution was heated until the
solid dissolved, allowed to cool, and filtered. The salt was
recrystallized from MeOH/2-propanol to provide 14 (0.28 g)
as white flakes: mp 210-211 °C. 1H NMR (DMSO-d6): δ 1.73
(s, 3H, CH3), 3.20 (s, 2H, CH2), 4.01-4.08 (d, J ) 19 Hz, 1H,
Ar-CH2-Ar) 4.14-4.19 (d, J ) 19 Hz, 1H, Ar-CH2-Ar), 7.25-
7.61 (brm, 8H, Ar-H). 13C NMR (DMSO-d6): δ 24.48, 34.96,
42.28, 46.80, 125.96, 127.08, 127.30, 128.49, 136.53, 139.08,
165.02. Anal. (C16H17N‚C2H2O4) C, H, N.
9-Am in om eth yl-10,10-dim eth yl-9,10-dih ydr oan th r acen e
Oxa la te (15). A solution of 10,10-dimethyl-9,10-dihydroan-
thracene-9-carboxamide34 (31, 0.45 g, 1.78 mmol) in anhydrous
THF (2 mL) was cooled (0 °C), and 1.0 M borane-THF complex
(8.90 mL, 8.90 mmol) was added under N2. The solution was
allowed to warm to room temperature and then heated at
reflux (8 h). The suspension was cooled (0 °C), and HCl (6.0
M, 4 mL) was cautiously added to the reaction mixture. The
reaction mixture was heated at reflux (1 h), allowed to cool to
room temperature, and concentrated under reduced pressure.
Water (20 mL) was added, and the resulting white suspension
was extracted with EtOAc (20 mL). The aqueous phase was
made basic with 10% NaOH and then extracted with EtOAc
(3 × 25 mL). The combined extracts were washed with water
and brine, dried (MgSO4), and concentrated under reduced
pressure to provide (0.35 g, 82%) a viscous oil. Oxalic acid (0.15
g, 1.61 mmol) was added to the amine in anhydrous acetone
(40 mL), and the suspension was heated until the oxalic acid
dissolved. The solution was allowed to cool and was filtered,
and the filter cake was washed with anhydrous acetone. The
solid was recrystallized from acetone to provide 15 as a white
2,3,7,11b-Tet r a h yd r od ib en zo[d ,e,h ]isoq u in olin e Ox-
a la t e (19). 2,3,7,11b-Tetrahydrodibenzo[d,e,h]isoquinolin-3-
one (30, 0.30 g, 1.42 mmol) in anhydrous THF (2 mL) was
cooled (0 °C) under N2. A 1.0 M solution of borane-THF
complex (7.10 mL, 7.10 mmol) was added in a dropwise
manner to the reaction mixture with constant stirring. The
reaction mixture was heated at reflux (6 h) and cooled to room
temperature. HCl (6.0 M, 4 mL) was cautiously added, and
the reaction mixture was heated at reflux (1 h), cooled to room
temperature, and concentrated under reduced pressure to
provide a white solid. Water (20 mL) was added, and the
suspension was extracted with Et2O (25 mL). The aqueous
layer was made basic with 10% NaOH and extracted with
EtOAc (3 × 25 mL). The combined extracts were washed with
water and brine, dried (MgSO4), and concentrated under
reduced pressure to provide (0.23 g, 83%) a colorless oil. The
oil was dissolved in anhydrous acetone (30 mL), and oxalic
acid (0.10 g, 1.15 mmol) was added. The suspension was heated
until the solid dissolved, it was cooled and filtered, and the
filter cake was washed with anhydrous acetone. The solid was
then recrystallized (EtOAc/MeOH) to provide 19 as white
1
powder: mp 187-189 °C. H NMR (DMSO-d6): δ 1.50 (s, 3H,
CH3), 1.73 (s, 3H, CH3), 2.87-2.90 (d, J ) 9 Hz, 2H, CH2),
4.21-4.26 (t, J ) 9 Hz, 1H, CH), 7.24-7.69 (brm, 8H, Ar-H).
13C NMR (DMSO-d6): δ 30.58, 36.85, 38.29, 43.80, 49.43,
126.67, 126.76, 127.71, 128.87, 134.41, 144.38. Anal. (C17H19N‚
C2H2O4) C, H, N.
1
crystals: mp 196-198 °C. H NMR (DMSO-d6): δ 3.38-3.46
11-Am in o-9,10-dih ydr o-9,10-eth an oan th r acen e Oxalate
(16). 10% Pd on charcoal (0.10 g) was added to 9,10-dihydro-
9,10-ethanoanthracen-11-one oxime13 (0.30 g, 1.27 mmol) in
MeOH (20 mL). The resulting suspension was hydrogenated
at 55 psi. (12 h). The catalyst was removed by filtration
through Celite, and solvent was evaporated under reduced
pressure to provide an oily solid. Water (10 mL) was added,
and the solution was made basic with 10% NaOH and
extracted with Et2O (3 × 25 mL). The combined extracts were
washed with water and brine, dried (MgSO4), and concentrated
under reduced pressure to provide an oily solid. The oily solid
was purified by medium-pressure column chromatography
using CHCl3/MeOH (9:1) to provide 16 (0.20 g, 71%) as a
viscous oil. The oil was dissolved in anhydrous acetone (35
mL), and oxalic acid (0.09 g, 1.00 mmol) was added. The
suspension was heated until the solid dissolved, and the
solution was allowed to cool; the precipitate was collected by
(t, J ) 12 Hz, 1H, CH), 3.81-4.10 (brm, 4H, CH2), 4.36 (brs,
2H, CH2), 7.10-7.41 (brm, 7H, Ar-H). 13C NMR (DMSO-d6):
δ 33.73, 35.76, 43.64, 44.28, 124.02, 124.60, 126.44, 126.94,
127.60, 128.65, 131.99, 136.38, 137.322, 165.18. Anal. (C16H15N‚
C2H2O4) C, H, N.
2-(Ben zyl)ben zyl Alcoh ol (20). A solution of 2-(benzyl)-
benzoic acid (2.0 g, 9.40 mmol) in anhydrous THF (5 mL) was
added under N2 at 0 °C to a stirred suspension of LiAlH4 (0.70
g, 18.8 mmol) in anhydrous THF (15 mL). The reaction mixture
was warmed to room temperature and heated at reflux (4 h).
The solution was cooled to room temperature, and water (0.75
mL), 10% NaOH (0.75 mL) and Celite (1.0 g) were cautiously
added. The mixture was filtered through a sintered glass filter,
and the filter cake was washed with CH2Cl2 (75 mL). The
filtrate was dried (MgSO4) and concentrated under reduced
pressure to provide 20 (1.8 g, 97%) as a colorless oil.27 The oil

1662 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8
Runyon et al.
was used in the next step without further purification. 1H
NMR (CDCl3): δ 1.87 (brs, 1H, OH), 4. 10 (s, 2H, CH2), 4.65
(s, 2H, CH2), 7.15-7.44 (brm, 9H, Ar-H). 13C NMR (CDCl3):
δ 39.07, 63.72, 126.77, 127.41, 128.55, 128.93, 129.16, 129.29,
24 was used without further characterization in the prepara-
tion of 11.
9,10-Dih yd r o-9,10-m eth a n oa n th r a cen e-9-ca r boxa m id e
(25). Thionyl chloride (1.0 g, 8.48 mmol) was added under N2
to a stirred solution of 9,10-dihydro-9,10-methanoanthracene-
9-carboxylic acid16 (1.0 g, 4.24 mmol) in anhydrous toluene (5
mL). The solution was heated at reflux (2 h), cooled to room
temperature, and concentrated under reduced pressure to
provide a pale yellow oil. Anhydrous THF (45 mL) was added,
and the solution was cooled (0 °C). NH3 was slowly bubbled
into the solution (0.5 h), and the solution was allowed to warm
to room temperature (1 h). Water (100 mL) was added, and
the suspension was extracted with CHCl3 (3 × 40 mL). The
organic extracts were combined, dried (MgSO4), and concen-
trated under reduced pressure to provide a white solid. The
solid was recrystallized from absolute EtOH to provide 25 (0.80
g, 85%) as white needles: mp 310-313 °C dec. 1H NMR
(CDCl3): δ 2.77-2.78 (d, J ) 1.6 Hz, 2H, CH2), 4.35 (s, 1H,
CH), 5.80 (brs, 2H, CONH2), 6.95-7.58 (brm, 8H, Ar-H). IR
(KBr): 3421 cm-1. Compound 25 was used without further
characterization in the preparation of 12.
131.17, 139.5, 140.54. IR (KBr): 3353 cm-1
.
2-(Ben zyl)ben za ld eh yd e (21). A solution of 2-(benzyl)-
benzyl alcohol (20, 1.8 g, 8.82 mmol) in anhydrous CH2Cl2,
(20 mL) was added over 30 min to a suspension of PCC (2.2 g,
10.1 mmol) and Celite (2.0 g) in anhydrous CH2Cl2 (50 mL) at
room temperature. The mixture was stirred for an additional
2 h. Anhydrous Et2O (150 mL) was added, and the dark
solution was filtered through a Florisil column. The brown
solution was concentrated under reduced pressure and purified
by medium-pressure column chromatography using petroleum
ether/acetone (9.5/0.5) to provide 21 as a colorless oil28 (1.40
g, 82%). 1H NMR (CDCl3): δ 4.48 (s, 2H, CH2), 7.17-7.90 (brm,
9H, Ar-H), 10.28 (s, 1H, COH). 13C NMR (CDCl3): δ 38.62,
126.9, 127.61, 129.19, 129.4, 132.27, 132.66, 134.54, 140.89,
143.60, 193.03. IR (KBr): 1699 cm-1
.
2-(2-Ben zylp h en yl)-tr a n s-n itr oeth en e (22). Ammonium
acetate (0.39 g, 5.10 mmol) was added to a stirred solution of
2-(benzyl)benzaldehyde (21, 1.0 g, 5.10 mmol) in nitromethane
(20 mL). The solution was heated at reflux (40 min), and the
yellow solution was cooled and concentrated under reduced
pressure to provide a yellow solid. The solid was recrystallized
from absolute EtOH to provide 22 (0.77 g, 63%) as yellow
needles: mp 98-100 °C. 1H NMR (CDCl3): δ 4.14 (s, 2H, CH2),
7.10-7.54 (brm, 10H, Ar-H, CHdCH), 8.29-8.33 (d, J ) 14
Hz, 1H, CHdCH). 13C NMR (CDCl3): δ 39.90, 127.14, 127.96,
128.15, 129.16, 129.36, 132.05, 132.59, 137.23, 138.47, 140.07,
2-(Ben zyl)a cetop h en on e (26). Thionyl chloride (2.8 g, 23.6
mmol) was added under N2 to a stirred solution of 2-(benzyl)-
benzoic acid (2.5 g, 11.8 mmol) in anhydrous benzene (50 mL).
The solution was heated at reflux (2 h), allowed to cool, and
the excess benzene and thionyl chloride were removed under
reduced pressure. The resulting yellow oil in anhydrous THF
(50 mL) was cooled (-78 °C), and methylmagnesium chloride
(3.0 M solution in THF) (4.0 mL, 12 mmol) was slowly added
under N2. The stirred mixture was allowed to warm to room
temperature (8 h). The solution was poured into water (100
mL) and extracted with EtOAc (3 × 75 mL). The combined
extracts were dried (MgSO4) and concentrated under reduced
pressure. The resulting oil was purified by Kuhgelrohr distil-
lation to provide a solid (bp 153 °C, 0.02 mmHg). The solid
was recrystallized from EtOAc/petroleum ether to provide 26
(1.5 g, 59%) as white needles: mp 47-49 °C (lit.30 mp 48-49
142.15. IR (KBr): 1512, 1351 cm-1
.
9,10-Dih yd r op h en a n th r en e-9-ca r boxa m id e (23). 9,10-
Dihydrophenanthrene-9-carboxylic acid14 (0.50 g, 2.21 mmol)
was dissolved in anhydrous benzene (10 mL) under N2 and
cooled (0 °C) in an ice bath. Thionyl chloride (0.79 g, 6.65
mmol) was added in a dropwise manner with continuous
stirring, the reaction mixture was heated at reflux (2 h) and
cooled to room temperature, and the solvent was removed
under reduced pressure to provide an oil. The oil was dissolved
in anhydrous THF (20 mL) and cooled (0 °C) in an ice bath.
Anhydrous NH3 was slowly bubbled into the stirred solution
for 0.5 h, and the mixture was stirred at room temperature (2
h). The solvent was removed under reduced pressure to give
an oil. Water (20 mL) was added, and the suspension was
extracted with EtOAc (3 × 25 mL). The combined extracts were
washed with water and brine and dried (MgSO4). Removal of
the solvent under reduced pressure gave an oil that solidified
on standing. The solid was purified by medium-pressure
column chromatography using CH2Cl2/acetone (8:2) to give a
colorless solid. The solid was then recrystallized from toluene
to give 23 (0.40 g, 80%) as colorless crystals: mp 144-145 °C.
1H NMR (CDCl3): δ 3.01-3.08 (m, 1H, CH), 3.31-3.38 (m,
1H, CH), 3.63-3.67 (t, J ) 6 Hz, 1H, CH), 7.21-7.80 (brm,
8H, Ar-H). 13C NMR (CDCl3): δ 32.36, 46.30, 124.18, 125.01,
127.97, 128.59, 128.73, 128.89, 129.58, 176.04.
1
°C). H NMR (CDCl3): δ 2.47 (s, 3H, CH3), 4.29 (s, 2H, CH2),
7.13-7.67 (brm, 9H, Ar-H). 13C NMR (CDCl3): δ 30.36, 39.79,
126.51, 126.77, 128.88, 129.54, 129.68, 131.95, 132.36. IR
(KBr): 1683 cm-1
.
3-Am in o-2-(2-ben zylp h en yl)-2-p r op a n ol (27). Trimeth-
ylsilyl cyanide (0.57 g, 5.71 mmol) was added under N2 to a
suspension of 2-(benzyl)acetophenone (26, 1.0 g, 4.76 mmol)
and ZnI (cat. amt.) in anhydrous CH2Cl2 (5 mL). The solution
was heated at reflux (3 h), allowed to cool to room temperature,
and poured into water (100 mL). The resulting suspension was
extracted with CH2Cl2 (3 × 60 mL), and the organic extracts
were combined, dried (MgSO4), and concentrated under re-
duced pressure to provide a pale yellow oil. The oil in
anhydrous THF (5 mL) was added to an ice-cold suspension
of LiAlH4 (0.54 g, 14.3 mmol) in anhydrous THF (25 mL). The
reaction mixture was allowed to warm to room temperature
and heated at reflux (8 h). The solution was cooled (0 °C), and
water (0.54 mL), 10% NaOH (0.54 mL), and Celite (1.25 g)
were added cautiously. The suspension was filtered through
a sintered glass filter and the filter cake washed with CH2Cl2
(100 mL). The filtrate was dried (MgSO4) and concentrated
under reduced pressure to provide a white solid. The solid was
recrystallized (toluene) to provide 27 (0.70 g, 61%) as fine white
needles: mp 114-116 °C. 1H NMR (CDCl3): δ 1.40 (s, 3H,
CH3), 2.72-2.77 (d, J ) 13 Hz, 1H, CH2-NH2), 3.25-3.28 (d,
J ) 13 Hz, 1H, CH2-NH2), 4.30-4.36 (d, J ) 16 Hz, 1H, Ar-
CH2-Ar), 4.40-4.46 (d, J ) 16 Hz, 1H, Ar-CH2-Ar), 7.08-
7.45 (brm, 9H, Ar-H). 13C NMR (CDCl3): δ 28.48, 40.40, 52.24,
75.24, 126.29, 126.76, 127.00, 127.6, 128.89, 129.34, 133.91.
IR (KBr): 3123 cm-1. Compound 27 was used without further
characterization in the preparation of 14.
Dib en zo[b,e]b icyclo[2.2.2]oct a d ien e-1-ca r b oxa m id e
(24). Thionyl chloride (1.9 g, 16.0 mmol) was added under N2
to a stirred solution of dibenzo[b,e]bicyclo[2.2.2]octadiene-1-
carboxylic acid15 (2.0 g, 8.00 mmol) in anhydrous toluene (10
mL). The solution was heated at reflux (2 h), cooled, and
concentrated under reduced pressure to provide a pale yellow
oil. The oil was dissolved in anhydrous THF (50 mL), cooled
(0 °C) in an ice bath, and NH3 was bubbled into the solution
for 0.5 h. The solution was allowed to warm to room temper-
ature (2 h). The white suspension was poured into water (50
mL) and extracted with CHCl3 (3 × 45 mL). The organic
extracts were combined, dried (MgSO4), and concentrated
under reduced pressure to provide a white solid. The solid
was recrystallized from absolute EtOH to provide 24 (1.6 g,
N-(Meth oxyca r bon yl)-9-a m in om eth yl-9,10-d ih yd r oa n -
th r a cen e (29). 9-(Aminomethyl)-9,10-dihydroanthracene (1,1
1.3 g, 6.00 mmol) and triethyl amine (1.25 mL, 9.01 mmol) in
anhydrous CH2Cl, (25 mL) were cooled (0 °C) under N2. Methyl
chloroformate (0.62 g, 6.61 mmol) was added to the reaction
mixture in a dropwise manner with constant stirring over 5
1
75%) as white crystals: mp 259-261 °C. H NMR (CDCl3): δ
1.75-1.80 (m, 2H, CH2), 1.89-1.93 (m, 2H, CH2), 4.39 (s,
1H, CH), 6.00 (brs, 1H, NH2), 6.19, (brs, 1H, NH2), 7.17-7.56
(brm, 8H, Ar-H). IR (KBr): 3440, 3179, 1655, cm-1. Compound

Geometry-Affinity Relationships of AMDA
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1663
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(5) Westkaemper, R. B.; Dukat, M.; Glennon, R. A. Molecular
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(6) Westkaemper, R. B.; Runyon, S. P.; Savage, J . E.; Roth, B. L.;
Glennon; R. A. Exploring the relationship between binding
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heptadine analogs at the 5-HT2A serotonin receptor. Bioorg. Med.
Chem. Lett. 2001, 11, 563-566.
min. The reaction mixture was gradually allowed to warm to
room temperature and then heated at reflux (0.5 h). The
reaction was allowed to cool to room temperature, and the
solvent was removed under reduced pressure to provide an
oily solid. Water (20 mL) was added, and the suspension was
extracted with EtOAc (3 × 25 mL). The combined extracts were
washed with water and brine, dried (MgSO4), and concentrated
under reduced pressure to provide a pale white solid. The solid
was recrystallized (EtOAc/petroleum ether) to provide 29 (1.4
g, 86%) as colorless crystals: mp 96-97 °C. 1H NMR (CDCl3):
δ 3.27-3.31 (t, J ) 6 Hz, 1H, CH), 3.66 (s, 3H, CH2), 3.87-
4.13 (m, 4H, Ar-CH2-Ar, CH, NH2), 4.69 (s, 1H, NH), 7.19-
7.49 (m, 8H, Ar-H). 13C NMR (CDCl3): δ 35.53, 44.89, 125.18,
126.79, 127.38, 127.68, 128.73, 132.14, 135.01, 136.08, 167.83.
Compound 29 was used without further characterization in
the preparation of 30.
(7) Runyon, S. P.; Savage, J . E.; Taroua, M.; Roth, B. L.; Glennon,
R. A.; Westkaemper, R. B. Infulence of chain length and
N-alkylation on the selective serotonin receptor ligand of 9-
(Aminomethyl)-9,10-dihydroanthracene. Bioorg. Med. Chem.
Lett. 2001, 11, 655-658.
2,3,7,11b-Tet r a h yd r od ib en zo[d ,h ,e]isoq u in olin -3-on e
(30). N-(Methoxycarbonyl)-9-amino-methyl-9,10-dihydroan-
thracene (29, 0.65 g, 2.43 mmol) was added to ice cold POCl3
(11 mL) under N2. The solution was allowed to warm to room
temperature and heated at reflux (24 h). The solution was
cooled (0 °C), and SnCl4 (0.94 g, 3.64 mmol) was added in a
dropwise manner. The reaction mixture was held at 0 °C for
4 h and slowly allowed to warm to room temperature (2 h).
The reaction mixture was poured onto ice (50 g), and the
suspension was allowed to stir (0.5 h). The suspension was
extracted with EtOAc (3 × 25 mL), and the combined extracts
were washed with water and brine and dried (MgSO4). The
solvent was removed under reduced pressure to provide a
brown solid that was purified by medium-pressure column
chromatography (CH2Cl2/acetone, 9:1). The resulting yellow
solid was recrystallized (EtOAc/petroleum ether) to provide 30
(0.38 g, 73%) as pale white crystals: mp 112-113 °C. 1H NMR
(CDCl3): δ 3.61-3.70 (t, J ) 12 Hz, 1H, CH), 4.04 (brs, 2H,
CH2), 4.24-4.26 (d, J ) 6 Hz, 1H, CH2), 4.27-4.29 (d, J ) 6
Hz, 1H, CH2), 7.21-8.07 (brm, 7H, Ar-H). 13C NMR (CDCl3):
δ 35.53, 44.89, 125.18, 126.79, 127.38, 127.68, 128.73, 132.14,
135.01, 136.08, 167.83. Compound 30 was used without further
characterization in the preparation of 19.
Molecu la r Mod elin g. Molecular modeling investigations
were conducted using the SYBYL molecular modeling package
(version 6.6, 1999, Tripos Associates, Inc., St. Louis, MO).
Molecular mechanics minimizations were performed using the
Tripos force field with Gasteiger-Huckel charges (distance
dependent dielectric constant ꢀ ) 4, nonbonded cutoff ) 8Å)
without constraints and were terminated at an energy gradient
of 0.005 kcal/mol. Systematic conformational analysis was
performed for structures having free rotation about single
bonds. Conformational analysis of cyclic systems was per-
formed using molecular dynamics based simulated annealing
followed by minimization of the resulting structures.
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Affin it y Det er m in a t ion s. Binding assays and data
analysis were performed as previously described using [3H]-
ketanserin as the radioligand and stably transfected NIH3T3
cells expressing the 5-HT2A receptor (GF-62 cells).32 All
compounds were tested as the water soluble salts except 17.
The test compound was introduced into buffered assay mix-
tures from DMSO stock solutions. Under these conditions,
homogeneous aqueous solutions of 17 were generated without
subjecting the aziridine to acidic conditions.
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(24) Snyder, S. E.; Aviles-Garay, F. A.; Chakraborti, R.; Nichols,
D. E.; Watts, V. J .; Mailman, R. B. Synthesis and evaluation of
6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta-
[1,2,3-ef][3]benzazepine,6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr-
[10,4a,4-cd]azepine, and 10-(aminomethyl)-9,10-dihydro-1,2-
dihydroxyanthracene as conformationally restricted analogues
of P-phenyldopamine. J . Med. Chem. 1995, 38, 2395-409.
(25) Andrews, P. R.; Lloyd, E. J . Molecular conformation and biologi-
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Rev. 1982, 2, 355-93.
Ack n ow led gm en t. This work was supported by
United States Public Health Service Grant MH57969
(R.B.W.), MH57635, MH01366 (B.L.R.), the NIMH
Psychoactive Drug Screening Program (B.L.R.), and
DA01642 (R.A.G.).
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