Further definition of the D1 dopamine receptor pharmacophore: synthesis of trans-6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphth[2,1-b]azepines as rigid analogues of beta-phenyldopamine.

Article abstract of DOI:10.1021/jm970157a

In an effort to define further the active geometry of the beta-phenyldopamine pharmacophore of certain dopamine D1 agonists, the title compounds have been synthesized as conformationally restricted homologues of the potent benzophenanthridine dopamine D1

Full text of DOI:10.1021/jm970157a

2140
J . Med. Chem. 1997, 40, 2140-2147
F u r th er Defin ition of th e D1 Dop a m in e Recep tor P h a r m a cop h or e: Syn th esis of
tr a n s-6,6a ,7,8,9,13b-Hexa h yd r o-5H-ben zo[d ]n a p h th [2,1-b]a zep in es a s Rigid
An a logu es of â-P h en yld op a m in e
Kitaw Negash,† David E. Nichols,*,† Val J . Watts,‡ and Richard B. Mailman‡
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences,
Purdue University, West Lafayette, Indiana 47907, and UNC Neuroscience Center & Departments of Pharmacology and
Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7250
Received March 10, 1997X
In an effort to define further the active geometry of the â-phenyldopamine pharmacophore of
certain dopamine D1 agonists, the title compounds have been synthesized as conformationally
restricted homologues of the potent benzophenanthridine dopamine D1 agonist dihydrexidine
4a . The dihydroxy secondary amine 5b was evaluated as a potential agonist, whereas the
N-methyl compounds 5a and 5c were hypothesized to be antagonists. Surprisingly, none of
the three compounds had high affinity for dopamine D1 or D2 receptors. A comparison of the
low-energy conformations of these molecules shows that the pendant phenyl ring of 5b is twisted
about 28° relative to that of the corresponding ring of 4a . Further, the additional methylene
used to expand the C ring of 5b projects toward the R face of the molecule, perhaps suggesting
that steric protrusion in this region of the molecule is not tolerated. Finally, the phenethylamine
fragment incorporated into these molecules deviates about 30° from the antiperiplanar
conformation postulated to be necessary for agonist activity. On the other hand, the potential
antagonist molecules 5a and 5c were compared with the dopamine D1 antagonist SCH 39166
2. The conformations of the former two structures differ quite dramatically from that of 2.
The most notable differences lie in the relative orientations of the pendant phenyl rings in the
two series, as well as the fact that the ethylamine fragment in 2 approximates a gauche
conformation, while the comparable orientation in 5a and 5c more nearly approaches an
antiperiplanar conformation. These findings will be used to refine further the model of the
dopamine D1 agonist receptor that we have previously developed.
Dopamine-mediated neurotransmission plays a role
in several psychiatric and neurological disorders, and
for this reason there has been great interest in the
search for novel dopamine receptor agonists and an-
tagonists. Dopamine receptors first were classified into
D1 and D2, subtypes on pharmacological and functional
grounds, including the coupling to the enzyme adenylate
cyclase.1 Recent molecular cloning studies have led to
the identification of five genes that code dopamine
receptor proteins, two in the D1 family (D1 and D5 or
D1B) and three in the D2 family (D2, D3, and D4).2-4
Despite much effort, the inability to elucidate the correct
three-dimensional orientation of the amino acid residues
at or near the binding site has been a drawback to the
design of selective and potent dopaminergic agents.
Thus, research still relies heavily on structure-activity
relationship (SAR) information generated from mol-
ecules synthesized on the basis of a lead compound.
A large number of structurally diverse compounds
have been found to be potent and selective ligands for
the D2 receptor. Many fewer D1-selective agents are
available, most in the phenyltetrahydrobenzazepine
class like the prototypic D1 selective antagonist SCH
23390 (1),5 its conformationally restricted analogue SCH
39166 (2),6 and the partial agonist SKF 38393 (3).7,8
Recent synthetic drug design work in our laboratories
has led to the design, synthesis, and characterization
of dihydrexidine (4a ) as the first high-affinity full
agonist at the D1 receptor.9,10 This work also made clear
that dopamine analogues containing a â-phenyl moiety
show greater affinity for the D1-like receptors.11,12 The
â-phenyl moiety is essential in conferring D1 affinity and
is also a major factor in selectivity of a drug for D1-like
vs D2-like receptors. The 10-bromo-6-methyl analogue
4b was also synthesized in order to investigate its
potential D1 antagonist activity. Although this molecule
did possess antagonist properties, it showed low affinity
(322 nM) for the D1 receptor.13
* Address correspondence to: Dr. David E. Nichols, Dept of Me-
dicinal Chemistry and Molecular Pharmacology, 1333 Pharmacy
Building, Purdue University, West Lafayette, IN 47907. Phone: (765)
494-1461. FAX: (765) 494-1414. E-mail: drdave@pharmacy.purdue.edu.
† Purdue University.
In an effort to define further the geometry of the
phenyl accessory region, we have now synthesized the
‡ University of North Carolina School of Medicine.
X Abstract published in Advance ACS Abstracts, J une 15, 1997.
S0022-2623(97)00157-X CCC: $14.00 © 1997 American Chemical Society

Definition of the D1 Dopamine Receptor Pharmacophore
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2141
Sch em e 1a
a
Reagents: (a) KOtBu, diethyl succinate, HCl; (b) H2, Pd-C; (c) P2O5/CH3SO3H; (d) H2, Pd-C, AcOH, HClO4; (e) NaOEt, reflux; (f)
NaOH, HCl; (g) Et3N, ClCOOC2H5, NaN3, toluene, reflux; (h) KOH, EtOH, reflux.
naphthobenzazepines 5a , 5b, and 5c as conformation-
ally rigid â-phenyldopamine analogues. Compound 5b
is the seven-membered C-ring analogue of 4a , while 5c
is the ring-expanded iodo derivative of 4b. The close
structural similarity between compound 4a and 5b
suggested that 5b would be a high-affinity agonist.
Conversely, it was also possible that 5a and 5c might
be antagonists at D1 receptors. On the other hand,
based on a model of the D1 receptor that we have
proposed,14 the greater twist of the pendant phenyl ring
(i.e., as compared to the corresponding ring in 4a ) leads
to the alternate hypothesis that these structural changes
will markedly decrease the affinity of 5a , 5b, and 5c.
The present studies were designed to distinguish among
these hypotheses and, in so doing, provide a better
understanding of the SAR of dopamine ligands possess-
ing a â-phenyl moiety.
and 9b. Modified Curtius rearrangement18 of the acids
and hydrolysis of the intermediate isocyanates with 20%
ethanolic KOH afforded the trans amines 10a and 10b.
These intermediates were alkylated with methyl bro-
moacetate to give 11a and 11b, respectively (Scheme
2). N-Tosylation with p-toluenesulfonyl chloride af-
forded 12a and 12b, respectively. Following the pro-
cedure of Rehman et al.,19 the esters were hydrolyzed
with cold 1 N methanolic KOH and reacidified. Conver-
sion of the acids to their acyl chlorides using oxalyl
chloride, followed by treatment with AlCl3 in dichlo-
romethane at -78 °C, afforded 13a and 13b. These
benzylic ketones were reduced with NaBH4. Treatment
of the resulting alcohols with BF3‚Et2O/Et3SiH20 gave
14a and 14b. N-Detosylation of 14a and 14b with Red-
Al (Aldrich) gave the naphthobenzazepines 15a and
15b. The hydrochloride salt of 15a was N-methylated
by treatment with 37% formalin solution and sodium
cyanoborohydride in methanol to give 16a . O-De-
methylation of 15b and 16a with boron tribromide
afforded the hydrobromide salts of 5b and 5a , respec-
tively. Both the hydrochloride and hydrobromide salts
of 5b were highly hygroscopic. Following the procedure
of Sy,21 16a was iodinated with AgSO4-I2 to give 17,
followed by ether cleavage with boron tribromide to
afford 5c.
Molecu la r Mod elin g
Ch em istr y
The synthesis of intermediate phenylaminotetralins
10a and 10b (Scheme 1) was based partially on earlier
work by Riggs.15 Friedel-Crafts acylation of benzene
with the respective benzoyl chlorides and aluminum
chloride at -78 °C, followed by Stobbe condensation of
the resulting benzophenones with diethyl succinate
following the method of Welch et al.,16 led to 6a and
6b, respectively. Catalytic hydrogenation, followed by
treatment of the products with Eaton’s17 reagent, af-
forded the tetralones 7a (cis and trans (5:1)) and 7b (cis),
respectively. Reduction of the tetralones with a second
catalytic hydrogenation in acetic acid in the presence
of a few drops of perchloric acid, followed by epimer-
ization of the cis products with sodium ethoxide, re-
sulted in trans 8a and 8b, respectively. Hydrolysis of
the resulting esters with NaOH afforded the acids 9a
All computations were performed using a Silicon
Graphics Indigo 2 Extreme generation system running
Spartan software (Version 4.1, Wavefunction, Inc.,
Irvine, CA). Structures were minimized as the free
bases in vacuo using semiempirical methods and AM1
potentials, as implemented in Spartan. Several differ-
ent starting geometries were examined in order to
identify global minima.
P h a r m a cology
All final compounds were tested for the ability to
compete with either [3H]SCH 23390 or [3H]spiperone
at D1 and D2 binding sites, respectively, in rat striatal
membranes. The values reported for the competitive
binding assays are the averages of three runs.

2142 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Negash et al.
Sch em e 2a
a
Reagents: (a) BrCH2COOCH3, K2CO3, DMF; (b) tosyl Cl, Et3N, CH2Cl2; (c) KOH, MeOH, HCl; (d) CH2Cl2, (COCl)2; DMT (cat.); (e)
AlCl3, CH2Cl2; (f) NaBH4, EtOH; (g) (Et)3SiH, BF3/Et2O; (h) Red-Al, toluene, reflux; (i) BBr3, CH2Cl2; (j) HCHO, NaCNBH3.
Ta ble 1. Dopamine Receptor Affinity of Naphthobenzazepines
5a -c
Ta ble 2. Torsion Angles τ1, τ2, and τ3 and Nitrogen to Meta
Oxygen Distance (N-O)a of the Global Minimum Energy
Conformations of Target Compounds 5a and 5c and Reference
Compounds Dihydrexidine (4a ) and SCH 39166 (2)
K0.5 (nM) ( SEMa
compd no.
5a
D1 affinity
D2 affinity
3950 ( 50
2850 ( 690
1380 ( 140
2.8
0.50
NA
>10,000
2220 ( 390
2960 ( 320
43.8
5b
5c
(+)-4a b
SCH 23390
CPZ
NAc
0.95
compd no.
τ1
τ2
τ3
N-O distance (Å)
a
All tests were performed as described in the methods on rat
2
-24.8
57.6
61.1
-41.6
-10.5
17.7
57.2
163.0
149.3
149.5
6.18
7.38
7.34
7.35
striatal membranes in the experimental section, using [3H]SCH
23390 as the D1 ligand and [3H]spiperone as the D2 ligand.
4a
5b
5c
Values from ref 26. c NA ) not applicable.
b
64.1
16.7
a
Straight-line distance from the amine nitrogen to the meta
Resu lts a n d Discu ssion
oxygen.
It is apparent from the data in Table 1 that 5a , 5b,
and 5c have very low affinity for either the D1 or D2
receptors, with K0.5 values 50-500 times higher than
that of 4a . These somewhat surprising data at first led
us to question the stereochemical assignments of the
target compounds. The magnitude of the NMR coupling
constants confirmed that the B/C ring junction remained
trans, however, and that no epimerization had occurred
during the reaction sequence. Furthermore, we have
recently reported that treatment of the acid chloride of
12a under more stringent conditions than those em-
ployed here had no effect on the trans geometry of the
B/C ring fusion.22 It was therefore concluded that the
loss of activity must be related to conformational or
steric effects.
bridge, thereby forming an azepine. The â-phenyl
moieties in both 5b and dihydrexidine are placed above
the plane of the catechol by nearly the same τ1 value
(ca. 60°) (Table 2). Nevertheless, the azepine ring of
5b allows the â-phenyl moiety to be more conforma-
tionally mobile than that of dihydrexidine 4a . This
relative mobility allows the â-phenyl moiety to twist
orthogonally (τ2) in the clockwise direction by about 18°,
with respect to the catechol ring, and 28°, with respect
to the â-phenyl moiety of dihydrexidine. If it is assumed
that the geometry of the agonist site of the D1 receptor
is complementary to the orientation of an active ligand
(in this case dihydrexidine 4a ), the larger twist angle
in 5b may force the â-phenyl moiety to intrude into an
excluded space in the D1 receptor.
Naphthobenzazepine 5b is simply a C-ring-expanded
analogue of dihydrexidine (4a ) in which the nitrogen is
tethered to the pendant phenyl moiety by an ethyl
A second possible explanation for the loss of activity
concerns the unknown consequences of the steric effect
of the ethyl tether between the nitrogen and the

Definition of the D1 Dopamine Receptor Pharmacophore
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2143
analogue 5c. Because neither compound had significant
affinity for the D1 receptor, an explanation was sought
from a comparison of the energy-minimized structures
of 5c versus 2. It was noted that a halogen at the “para”
position of the ethylamine side chain of â-phenyldopam-
ines increases the D1 affinity of antagonists.24 Although
there was a relative improvement in D1 affinity of 5c
versus 5a (Table 1), the K0.5 values were very high and
did not differ enough to discriminate between the two
compounds.
Superimposition of energy-minimized structures of 5c
and 2 and a review of the torsion angles (Table 2)
reveals that the two phenyl moieties orient to opposite
faces of the plane of superposition. The phenyl moiety
of 5c is placed approximately 64° above the plane of the
substituted aromatic ring and twisted slightly (τ2
)
16.7°) in the clockwise direction. On the other hand,
the phenyl moiety of 2 is below the plane of the
substituted aromatic ring and is twisted about 42° in
the anticlockwise direction.
F igu r e 1. Face and edge-on views of the energy-minimized
structures of dihydrexidine (4a ; left) and the naphthobenza-
zepine 5b (right). Note differences in the twist of the nonsub-
stituted (pendant) phenyl ring, as well as the expanded steric
profile of the R face of the azepine ring (ring C) in 5b as
compared to 4a . The arrow on 5b points to the additional
methylene group of the azepine ring that protrudes toward
the R face of the molecule.
Another apparent difference between 5c and 2 is the
orientation of the ethylamine side chain fragments,
where the former has a nearly extended trans â-rotamer
(τ3 ) 150°), while the latter resides as a gauche (cisoid)
rotamer (τ3 ) 57°). These orientations result in different
nitrogen to oxygen distances of 7.35 and 6.18 Å for 5c
and 2, respectively. Moreover, superposition of the
substituted aromatic rings of energy-minimized struc-
tures showed not only a nearly perpendicular orienta-
tion of the two phenyl accessory rings but that the two
nitrogens were placed at a distance of 1.56 Å from each
other, another factor that may contribute to the absence
of activity in 5a and 5c at the D1 receptor.
In summary, the dramatic differences in conformation
between compound 2 and compounds 5a and 5c are
sufficient to explain the lack of D1 affinity for the latter
compounds. On the other hand, the conformational
differences between the highly potent D1 agonist dihy-
drexidine 4a and its C-ring-expanded analogue 5b are
less striking, but may provide the explanation for the
low affinity of the latter compound. The only other
obvious structural difference is the increased steric bulk
of the ethyl bridge tethering the nitrogen atom to the
pendant phenyl ring, which protrudes somewhat behind
the plane of the molecule. These results, when inte-
grated with our earlier studies, will continue to refine
our concept of the D1 agonist pharmacophore.14
pendant phenyl ring of 5b, as compared to the analogous
methylene unit in 4a . Superposition of the energy-
minimized structures of 4a and 5b shows that not only
is the pendant phenyl moiety of 5b clearly twisted
orthogonally with respect to that of dihydrexidine, but
also that the ethyl bridge of 5b protrudes below the
superimposition plane (see Figure 1). Because this area
is adjacent to the nitrogen atom (a presumed major site
for receptor interaction), it seems possible that an
unfavorable steric effect here might interfere with
ligand binding.
It is obvious that the azepine ring dictates not only
the orientation of the â-phenyl moiety but also the
conformation of the phenethylamine fragment in 5b. As
listed in Table 2, there is about 13° (τ3) more deviation
from a trans-antiperiplanar conformation for 5b than
in dihydrexidine 4a . It has been suggested that a fully
extended trans â-rotamer conformation of the ethyl-
amine fragment is important for agonist activity.11,23
Thus, the increased deviation of the ethylamine side
chain from an antiperiplanar conformation could also
be an additional factor to explain partially the attenu-
ated activity of 5b. Indeed, it may be that all three of
these factors are operating in concert.
Exp er im en ta l Section
Melting points were determined with a Thomas-Hoover
apparatus and are uncorrected. 1H NMR spectra were ob-
tained on a Varian VXR-500S (500 MHz) NMR instrument in
CDCl3 with TMS as an internal standard, except as noted.
High-resolution mass spectra were obtained on a Kratos MS50,
and chemical ionization mass spectra were obtained on a
Finnigan 4000. Elemental analyses were performed by the
Purdue University microanalysis laboratory and are within
(0.4% of the calculated values.
(E,Z)-3-Ca r beth oxy-4-(3′-m eth oxyp h en yl)-4-p h en yl-4-
bu ten oic Acid (6a ). To a solution of 3-methoxybenzoic acid
(25 g, 164.3 mmol) in 250 mL of dichloromethane was added
oxalyl chloride (54.76 g, 410.7 mmol) dropwise at ice-water
bath temperature. The reaction was allowed to warm to room
temperature and stirred for 1 h. The solvent and excess oxalyl
chloride were removed by rotary evaporation. The resulting
acid chloride was mixed with dry benzene (250 mL) and cooled
in an ice-water bath. Aluminum chloride powder (20.6 g,
154.3 mmol) was added dropwise using a powder addition
One could also consider a superposition of 5c over 2
whereby the unsubstituted phenylbenzazepine moiety
of 5c is superimposed over the analogous hydroxychloro-
substituted portion of compound 2. While such a view
gives good superposition of the template backbones for
both molecules, it ignores the likelihood that the recep-
tor will interact with the polar hydroxy and halo
substituents in a similar region of space, and this
approach was therefore not given serious consideration
in our search for an explanation of the different biologi-
cal activities.
The low dopamine D1 affinity of 4b (322 nM)13 and,
in contrast, the remarkably high affinity of the phenyl-
benzazepine SCH 23390 (1)5 and its conformationally
rigid analogue SCH 39166 (2)6 prompted the synthesis
and evaluation of naphthobenzazepine 5a and its 3-iodo

2144 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Negash et al.
funnel. The mixture was then allowed to stir overnight at
room temperature and poured into ice-water. The two phases
were separated, and the organic layer was washed with 2 N
HCl (150 mL) and water (3 × 150 mL). After drying (MgSO4)
and filtration, the solvent was removed by rotary evaporation
and the residue was dissolved in freshly distilled tert-butyl
alcohol. Powdered potassium tert-butoxide (Aldrich) (12.7 g,
119.2 mmol) was added into the tert-butyl alcohol solution,
followed by dropwise addition of diethyl succinate (25.6 g, 146
mmol) over 1 h. The reaction mixture was heated at reflux
overnight, cooled, poured into ice-water, and extracted with
diethyl ether (2 × 120 mL), followed by ethyl acetate (1 × 160
mL). Upon acidification of the aqueous layer with 6 N HCl,
an oil separated which was extracted with dichloromethane
(3 × 100 mL). After drying (MgSO4) and filtration, the solvent
was removed to yield 50.88 g (91%) of crude 6a : IR (neat) 1706
cm-1; CIMS (isobutane) M + 1 341. The material was
sufficiently pure, as determined by TLC, to carry on to the
next step without further purification.
and the crude product was dissolved in 30 mL of absolute
ethanol. This solution was added to a solution of freshly
prepared sodium ethoxide in ethanol (4.0 g of sodium metal
and 80 mL of ethanol). The reaction was heated at reflux for
10 h and then cooled and poured into ice water. Extraction
with diethyl ether (3 × 50 mL) followed by washing with water,
drying (MgSO4), and solvent removal afforded 4.24 g (73.8%
yield) of the crude epimerized product. Recrystallization from
ethanol afforded the pure product having all analytical data
identical to 8a obtained from trans-7a .
(()-tr a n s-Eth yl 1-P h en yl-6,7-dim eth oxy-1,2,3,4-tetr ah y-
d r o-2-n a p h th oa te (8b). Trans ester 8b was obtained (95%
yield) by epimerization of 7b25 with a solution of sodium
ethoxide in ethanol as described for 8a (obtained from cis-
7a ): IR (KBr) 1725 cm-1; CIMS (isobutane) M + 1 341; 1H
NMR (CDCl3) δ 7.20 (m, 3, ArH), 7.10 (m, 2, ArH), 6.65 (s, 1,
ArH), 6.25 (s, 1, ArH), 4.36 (d, 1, Ar2CH, J ) 9.4 Hz), 4.04 (q,
2, CH2), 3.86 (s, 3, OCH3), 3.59 (s, 3, OCH3), 2.84 (m, 3,
CHCOO, ArCH2), 1.59 (m, 2, ArCCH2), 1.12 (t, 3, CH3). Anal.
(C20H22O3) C, H.
(()-cis- an d tr a n s-1-P h en yl-2-car beth oxy-4-oxo-7-m eth -
oxy-1,2,3,4-t et r a h yd r on a p h t h a len e (7a ). A solution of
crude 6a (50 g, 146.9 mmol) in 500 mL of 95% ethanol
containing 5 g of 10% Pd-C catalyst was shaken at room
temperature under 50 psig of hydrogen overnight. The
catalyst was removed by filtration through Celite, and the
solvent was removed by rotary evaporation to yield a viscous
oil. The oil was stirred in 158 mL of 10% P2O5/methanesulfonic
acid for 10 h at room temperature. The reaction mixture was
poured into 350 mL of ice-water and extracted with ethyl
acetate (3 × 100 mL). The organic layer was washed with
saturated sodium bicarbonate solution (2 × 80 mL) and water
(2 × 100 mL). After drying (MgSO4) and filtration, the solvent
was removed to give a dark oil. This material was chromato-
graphed over 200 g of silica gel, eluting with hexane-ethyl
acetate (3:1) under a slight nitrogen pressure. Fractions
containing material with Rf 0.43 in hexane-ethyl acetate (3:
2) were combined and evaporated to give an oil which was
recrystallized from diethyl ether to provide 8.58 g (18%) of
trans-7a : mp 100-101 °C; IR (KBr) 1680, 1730 cm-1; CIMS
(()-t r a n s-1-P h e n yl-7-m e t h oxy-1,2,3,4-t e t r a h yd r o-2-
n a p h th oic Acid (9a ). Ester 8a (2.09 g, 7.4 mmol) was heated
at reflux for 10 h with 25 mL of 2 N aqueous NaOH solution
containing 5 mL of ethanol. The reaction mixture was then
poured into water, acidified with 6 N HCl, and extracted with
dichloromethane (3 × 50 mL). After drying (MgSO4), filtration
and removal of the solvent afforded 1.88 g (90%) of 9a which
was recrystallized from benzene-hexanes: mp 148-149 °C;
1
IR (KBr) 1709 cm-1; CIMS (isobutane) M + 1 283; H NMR
(CDCl3) 7.26-7.29 (m, 2, ArH), 7.20-7.24 (m, 1, ArH), 7.12
(d, 2, ArH, J ) 7.8 Hz), 7.05 (d, 1, ArH, J ) 8.4 Hz), 6.72 (dd,
1, ArH, J ) 2.6, 8.5 Hz), 6.33 (s, 1, ArH), 4.40 (d, 1, Ar2CH, J
) 8.6 Hz), 3.61 (s, 3, OCH3), 2.90 (m, 3, ArCH2, CHCOO), 2.19
(m, 1, ArCCH), 2.0 (m, 1, ArCCH). Anal. (C19H20O3) C, H.
(()-tr a n s-1-P h en yl-6,7-d im eth oxy-1,2,3,4-tetr a h yd r o-2-
n a p h th oic Acid (9b). Trans acid 9b was obtained (80% yield)
from 8b as described for 9a and recrystallized from benzene-
hexanes: mp 130-132 °C; IR (KBr) 1709 cm-1; CIMS (isobu-
tane) M + 1 313; 1H NMR (CDCl3) δ 7.25-7.3 (m, 2, ArH),
7.2-7.23 (m, 1, ArH), 7.1 (d, 2, ArH, J ) 7.1 Hz), 6.6 (s, 1,
ArH), 6.26 (s, 1, ArH), 4.4 (d, 1, Ar2CH, J ) 7.9 Hz), 3.87 (s, 3,
OCH3), 3.6 (s, 3, OCH3), 2.86-2.92 (m, 3, CHCOO, ArCH2),
2.11-2.17 (m, 1, ArCCH), 1.99-2.06 (m, 1, ArCCH). Anal.
(C19H20O4) C, H.
1
(isobutane) M + 1 325; H NMR (500 MHz, CDCl3) δ 8.07 (d,
1, ArH, J ) 8.8 Hz), 7.25-7.32 (m, 2, ArH), 7.1 (d, 2, ArH, J
) 6.3 Hz), 6.86 (d, 1, ArH, J ) 8.8 Hz), 6.39 (s, 1, ArH), 4.6 (d,
1, Ar2CH, J ) 7.3 Hz), 3.87 (q, 2, COCH2, J ) 7.1 Hz), 3.71 (s,
3, OCH3), 3.29-3.33 (m, 1, CCHCO), 2.89 (dd, 1, ArCOCH, J
) 8.5, 17.03 Hz), 2.75 (dd, 1, ArCOCH, J ) 4.4, 17.1 Hz), 1.0
(t, 3, CH3, J ) 7.1 Hz). Anal. (C20H20O4) C, H.
(()-tr a n s-1-P h en yl-7-m eth oxy-2-a m in o-1,2,3,4-tetr a h y-
d r on a p h th a len e (10a ). Following the Weinstock modifica-
tion of the Curtius rearrangement,18 a solution of 9a (5.0 g,
17.7 mmol) in 60 mL of dry acetone was cooled to 0 °C in an
ice-salt bath. Triethylamine (1.83 g, 17.9 mmol) in 10 mL of
acetone was added all at once, and the reaction was stirred
for 30 min. Ethyl chloroformate (3.15 g, 17.9 mmol) in 10 mL
of acetone was added dropwise over 5 min, and the mixture
was stirred at 0 °C for 1 h. A solution of sodium azide (2.76
g, 17.7 mmol) in 20 mL of water was then added dropwise over
10 min. The mixture was stirred at 0 °C for 1 h, poured into
ice-water, and extracted with toluene (3 × 300 mL). After
drying (MgSO4) and filtration, the stirred organic solution was
heated on a steam bath for 2 h. The reaction was shown to
be complete by IR. The toluene was removed by rotary
evaporation to give a yellow oil. The oil was redissolved in 60
mL of ethanolic potassium hydroxide and heated at reflux for
48 h. The ethanol was removed by rotary evaporation, and
the residue was partioned between water (200 mL) and diethyl
ether (3 × 200 mL). The ether solution was then extracted
with 2 N HCl (2 × 100 mL). The aqueous solution was washed
with 100 mL of ether, basified to pH 9.5 with ammonia, and
extracted with dichloromethane (2 × 100 mL). The organic
solution was dried (MgSO4), the solid was filtered, and removal
of the solvent afforded 3.63 g (81%) of free base 10a as a pale
yellow oil. A portion of the free base was converted to the
hydrochloride salt and recrystallized from ethanol-ether: mp
The mother liquor obtained after filtration of trans-7a was
concentrated to give 23.8 g (50%) of cis-7a as a brown oil. A
small amount of the oil was purified by centrifugal thin-layer
chromatography on a silica rotor using hexane-ethyl acetate
(4:1) as the developing solvent: IR (neat) 1674, 1728 cm-1
;
1
CIMS (isobutane) M + 1 325; H NMR (500 MHz, CDCl3) δ
8.12 (d, 1, ArH, J ) 8.8 Hz), 7.22-7.24 (m, 3, ArH), 6.96-7.0
(m, 2, ArH), 6.92 (d, 1, ArH, J ) 8.8 Hz), 6.24 (s, 1, ArH), 4.78
(d, 1, Ar2CH, J ) 4.8 Hz), 4.1 (q, 2, COCH2, J ) 7.1 Hz), 3.8
(s, 3, OCH3), 3.55 (tt, 1, CCHCO, J ) 19.4, 4.8,Hz), 2.9 (dd, 1,
ArCOCH, J ) 4.2, 18.7 Hz), 1.22 (t, 3, CH3, J ) 7.1 Hz).
(()-tr a n s-Eth yl 1-P h en yl-7-m eth oxy-1,2,3,4-tetr ah ydr o-
2-n a p h th oa te (8a ). (I) F r om tr a n s-7a . Trans keto ester
7a (6.0 g, 18.5 mmol) was dissolved in 200 mL of acetic acid
containing 0.5 mL of perchloric acid and 500 mg of 10% Pd-C
catalyst and shaken for 8 h at room temperature under 50
psig of hydrogen. Solid potassium carbonate was added to
neutralize the perchloric acid. The catalyst was removed by
filtration, the solvent was removed by rotary evaporation, and
the residue was recrystallized from ethanol to give 5 g (87%)
of 8a : mp 56-57 °C; IR (KBr pellet) 1724 cm-1; CIMS
1
(isobutane) M + 1 311; H NMR (CDCl3) δ 7.23-7.26 (m, 2,
ArH), 7.16-7.20 (m, 1, ArH), 7.09-7.11 (m, 2, ArH), 7.02 (d,
1, ArH, J ) 8.4 Hz), 6.68 (d, 1, ArH, J ) 8.4 Hz), 6.28 (s, 1,
ArH), 4.34 (d, 1, Ar2CH, J ) 9.5 Hz), 3.98 (q, 2, OCH2, J ) 7.1
Hz), 3.58 (s, 3, OCH3), 2.82-2.91 (m, 3, CHCOO, ArCH2),
2.10-2.15 (m, 1, ArCCH), 1.94-2.03 (m, 1, ArCCH), 1.04 (t,
3, CH3, J ) 7.1 Hz). Anal. (C20H22O3) C, H.
1
262-263 °C; CIMS (isobutane) M + 1 254; H NMR (CDCl3,
free base) δ 7.32 (m, 2, ArH), 7.26 (m, 1, ArH), 7.17 (d, 2, ArH,
J ) 8.1 Hz), 7.26 (d, 1, ArH, J ) 8.4 Hz), 6.7 (d, 1, ArH, J )
8.6 Hz), 6.24 (s, 1, ArH), 3.69 (d, 1, Ar2CH, J ) 8.9 Hz), 3.60
(s, 3, OCH3), 3.19-3.22 (m, 1, CHN), 2.87 (m, 2, ArCH2), 2.06
(II) F r om cis-7a . Cis keto ester 7a (6.0 g, 18.5 mmol) was
reduced by catalytic hydrogenation as described for trans-7a ,

Definition of the D1 Dopamine Receptor Pharmacophore
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2145
acetate: mp 123-125 °C; CIMS (isobutane) M + 1 510; IR
(m, 1, CHCN), 1.74 (m, 1, CHCN), 1.4 (b s, 2, NH2). Anal.
(C17H20NOCl) C, H, N.
1
(KBr) 1750, 1153 cm-1; H NMR (500 MHz, CDCl3) δ 7.52 (d,
2, ArH, J ) 8.3 Hz), 7.08-7.14 (m, 5, ArH), 6.92 (d, 1, ArH, J
) 6.8 Hz), 6.58 (s, 1, ArH), 6.05 (s, 1, ArH), 4.35 (d, 1,
NCHCOO, J ) 18.0 Hz), 4.82 (d, 1, Ar2CH, J ) 9.3 Hz), 3.96-
4.02 (m, 1, CHN), 3.83 (s, 3, OCH3), 3.76 (d, 1, NCHCOO, J )
18.1 Hz), 3.69 (s, 3, OCH3), 3.53 (s, 3, OCH3), 2.93-3.02 (m, 1,
ArCH), 2.78-2.83 (m, 1, ArCH), 2.39 (s, 3, ArCH3), 2.22-2.28
(m, 1, CHCN), 1.92-2.0 (m, 1, CHCN). Anal. (C28H31NO6S)
C, H, N.
(()-tr a n s-1-P h en yl-6,7-d im eth oxy-2-a m in o-1,2,3,4-tet-
r a h yd r on a p h th a len e (10b). The free base 10b was obtained
(80% yield) from 9b as described for 10a , and the hydrochloride
salt was recrystallized from ethanol: mp 246-248 °C; CIMS
1
(isobutane) M + 1 284; H NMR (CDCl3, free base) δ 7.32 (t,
2, ArH, J ) 7.4 Hz), 7.23-7.27 (m, 1, ArH), 7.18 (d, 2, ArH, J
) 7.7 Hz), 3.87 (s, 3, OCH3), 3.68 (d, 1, Ar2CH, J ) 8.42 Hz),
3.58 (s, 3, OCH3), 3.17-3.01 (m, 1, CHN), 3.82-3.01 (m, 2,
ArCH2), 2.02-2.08 (m, 1, CHCN), 1.69-1.77 (m, 1, CHCN).
Anal. (C18H22NO2Cl) C, H, N.
(()-tr a n s-2-Meth oxy-7-(p-tolylsu lfon yl)-5,6,6a ,7,8,13a -
h exa h yd r oben zo[d ]n a p h th [2,1-b]a zep in -9-on e (13a ). Es-
ter 12a (710 mg, 1.48 mmol) was stirred at room temperature
with 20 mL of 1 N methanolic KOH for 6 h. The methanol
was removed in vacuo, and the residue was dissolved in water
(50 mL). The aqueous solution was then acidified with 2 N
HCl and extracted with chloroform (3 × 30 mL). The aqueous
layer was discarded, and the combined organic extracts were
washed with water (3 × 30 mL) and brine, dried (MgSO4), and
evaporated in vacuo to give a white foam. This product was
redissolved in 10 mL of dichloromethane, and oxalyl chloride
(277 mg, 2.2 mmol) was added dropwise at room temperature
into the dichloromethane solution. DMF (2 drops) was added,
and the mixture was stirred for 1 h. The solvent and excess
oxalyl chloride were removed in vacuo, and the residue was
redissolved in 10 mL of dichloromethane. The solution was
then dropped into a suspension of AlCl3 (592 mg, 4.44 mmol)
in dichloromethane (5 mL) at -78 °C. The temperature was
raised to -15 °C over 2 h, and the reaction mixture was poured
onto ice. The organic phase was separated and washed with
10 mL of 5% HCl, concentrated NaHCO3 solution, and brine.
The organic solution was dried (MgSO4) and evaporated in
vacuo. The crude product was purified by centrifugal thin-
layer chromatography on a silica rotor using 20% ethyl acetate
in hexane to afford 121 mg (66%) of 13a : mp 146-148 °C; IR
(KBr) 1686, 1261 cm-1; CIMS (isobutane) M + 1 448; 1H NMR
(500 MHz, CDCl3) δ 7.26-7.3 (m, 1, ArH), 7.16 (d, 2, ArH),
7.02-7.11 (m, 3, ArH), 6.96 (d, 1, ArH), 6.9 (d, 2, ArH), 6.77
(dd, 1, ArH, J ) 2.6, 8.5 Hz), 6.42 (s, 1, ArH), 4.66 (d, 1,
COCHN, J ) 20.1 Hz), 4.37 (d, 1, Ar2CH, J ) 11.9 Hz), 4.1-
4.17 (m, 2, COCHN, CHN), 3.61 (s, 3, OCH3), 3.09-3.16 (m,
1, ArCH), 2.86-2.91 (m, 1, ArCH), 2.35-2.4 (m, 1, CHCN),
(()-tr a n s-N-(7-Met h oxy-1-p h en yl-1,2,3,4-t et r a h yd r o-
n a p h th a len -2-yl)glycin e, Meth yl Ester (11a ). To a solution
of 1.7 g (6.69 mmol) of 10a in 50 mL of dry DMF was added
1.99 g (14.3 mmol) of anhydrous potassium carbonate, and the
mixture was cooled to -5 °C. Methyl bromoacetate (1.02 g,
6.69 mmol) was added, and the reaction mixture was stirred
for 30 min at -5 °C and for an additional 4 h at room
temperature. The mixture was then poured into water and
extracted with diethyl ether (3 × 100 mL). The ether solution
was washed with water and dried (MgSO4), and the solvent
was removed by rotary evaporation to give a brown oil.
Purification of the oil (less than 1 g at a time) by centrifugal
thin-layer chromatography on a 4 mm silica rotor, using 30%
ethyl acetate-hexane in an ammonia atmosphere, afforded
1.85 g (85%) of free base 11a . A portion of the free base was
converted to the hydrochloride salt and recrystallized from
methanol-ether: mp 173-174 °C; CIMS (isobutane) M + 1
326; 1H NMR (CDCl3, free base) δ 7.3-7.34 (m, 2, ArH), 7.25-
7.28 (m, 1, ArH), 7.13-7.16 (m, 2, ArH), 7.05 (d, 1, ArH, J )
8.4 Hz), 6.6 (dd, 1, ArH, J ) 2.4, 8.4 Hz), 6.27 (s, 1, ArH), 3.9
(d, 1, Ar2CH, J ) 7.8 Hz), 3.64 (s, 3, OCH3), 3.61 (s, 3, OCH3),
3.42 (dd, 2, NCH2CO, J ) 17.3 Hz), 2.97-3.01 (m, 1, ArCH),
2.86-2.9 (m, 2, ArCH, CHN), 2.07-2.12 (m, 1, CHCN), 1.62-
1.7 (m, 1, CHCN). Anal. (C20H24NO3Cl) C, H, N.
(()-tr a n s-N-(6,7-Dim et h oxy-1-p h en yl-1,2,3,4-t et r a h y-
d r on a p h th a len -2-yl)glycin e, Meth yl Ester (11b). The free
base 11b was obtained (83%) from 10b as described for 11a .
A portion of the free base was converted to the hydrochloride
salt and recrystallized from methanol: mp 197-198 °C; CIMS
1
(isobutane) M + 1 356; H NMR (CDCl3, free base) δ 7.33 (t,
2.31 (s, 3, ArCH3), 1.99-2.06 (m, 1, CHCN). Anal. (C26H25
NO4S) C, H, N.
-
2, ArH, J ) 7.6 Hz), 7.26 (t, 1, ArH, J ) 7.4 Hz), 7.13 (d, 2,
ArH, J ) 7.8 Hz), 6.6 (s, 1, ArH), 6.22 (s, 1, ArH), 3.9 (d, 1,
Ar2CH, J ) 7.1 Hz), 3.86 (s, 3, OCH3), 3.65 (s, 3, OCH3), 3.6
(s, 3, OCH3), 3.47 (d, 1, NCHCOO, J ) 17.2 Hz), 3.4 (d, 1,
NCHCOO, J ) 17.3 Hz), 2.94-2.99 (m, 1, ArCH), 2.84-2.88
(m, 2, ArCH, CHN), 2.02-2.08 (m, 1, CHCN), 1.83 (b s, 1, NH),
1.63-1.7 (m, 1, CHCN). Anal. (C21H26NO4Cl) C, H, N.
(()-tr a n s-N-(7-Met h oxy-1-p h en yl-1,2,3,4-t et r a h yd r o-
n a p h th a len -2-yl)-N-(p-tolylsu lfon yl)glycin e, Meth yl Es-
ter (12a ). To a solution of 1.3 g (3.99 mmol) of 11a in 20 mL
of dichloromethane was added triethylamine (0.97 mL, 6.96
mmol) in 3 mL of dichloromethane and freshly recrystallized
p-toluenesulfonyl chloride (907 mg, 4.73 mmol), and the
reaction mixture was stirred at room temperature for 48 h.
The mixture was poured into water (50 mL), and the layers
were separated. The aqueous layer was further extracted with
dichloromethane (2 × 20 mL), and the organic layers were
combined, washed with 1 N HCl (30 mL), and dried (MgSO4).
Filtration and removal of the solvent afforded the crude ester.
Column chromatography of the ester over 30 g of silica gel,
using 20% ethyl acetate in hexane as the developing solvent,
afforded 1.5 g (76.8%) of 12a as a gum: CIMS (isobutane) M
+ 1 480; IR (neat) 1737, 1155 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.49 (d, 2, ArH, J ) 7.3 Hz), 7.07-7.14 (m, 5, ArH), 7.0 (d,
1, ArH, J ) 8.4 Hz), 6.66 (dd, 1, ArH, J ) 8.4, 2.7 Hz), 6.16 (s,
1, ArH), 4.12-4.17 (m, 2, NCHCOO, Ar2CH), 4.0-4.05 (m, 1,
CHN), 3.75 (d, 1, NCHCOO, J ) 18.2 Hz), 3.67 (s, 3, OCH3),
3.56 (s, 3, OCH3), 2.92-3.0 (m, 1, ArCH), 2.8-2.86 (m, 1,
ArCH), 2.37 (s, 3, ArCH3), 2.24-2.3 (m, 1, CHCN), 1.9-2.0
(m, 1, CHCN). Anal. (C27H29NO5S) C, H, N.
(()-t r a n s-2,3-Dim e t h oxy-7-(p -t olylsu lfon yl)-5,6,6a ,
7,8,13a -h exa h yd r ob en zo[d ]n a p h t h [2,1-b]a zep in -9-on e
(13b). Product 13b was obtained (65%) from 12b as described
for 13a and recrystallized from ethanol-ether: mp 180-182
°C; IR (KBr) 1682, 1261 cm-1; CIMS (isobutane) M + 1 478;
1H NMR (500 MHz, CDCl3) δ 7.29 (t, 1, ArH, J ) 7.6 Hz), 7.19
(d, 2, ArH, J ) 8.2 Hz), 7.05-7.08 (m, 2, ArH), 6.98 (d, 1, ArH,
J ) 7.5 Hz), 6.93 (d, 2, ArH, J ) 8.1 Hz), 6.65 (s, 1, ArH), 6.38
(s, 1, ArH), 4.68 (d, 1, COCHN, J ) 20.1 Hz), 4.38 (d, 1, Ar2-
CH, J ) 11.7 Hz), 4.19 (d, 1, COCHN, J ) 20.1 Hz), 4.13 (td,
1, CHN, J ) 11.7, 2.7 Hz), 3.9 (s, 3, OCH3), 3.61 (s, 3, OCH3),
3.14-3.22 (m, 1, ArCH), 2.84-2.9 (m, 1, ArCH), 2.37-2.44 (m,
1, CHCN), 2.33 (s, 3, ArCH3), 2.01-2.1 (m, 1, CHCN). Anal.
(C27H27NO5S) C, H, N.
(()-tr a n s-2-Meth oxy-7-(p-tolylsu lfon yl)-6,6a ,7,8,9,13b-
h exa h yd r o-5H-ben zo[d ]n a p h th [2,1-b]a zep in e (14a ). To
a solution of 13a (535.7 mg, 1.2 mmol) in 16 mL of absolute
ethanol was added sodium borohydride (90 mg, 2.4 mmol) at
room temperature. The mixture was stirred overnight, and
the reaction was quenched with 5 mL of water. The solvent
was removed in vacuo, the aqueous mixture was extracted with
chloroform (3 × 15 mL), washed with brine, and dried (MgSO4),
and the solvent was removed in vacuo to give the crude alcohol.
To the alcohol was added, with stirring, 5 mL (41.0 mmol) of
freshly distilled boron triflouride etherate. A few drops of
dichloromethane were added dropwise until the suspension
went into solution, followed by 2 mL (12.6 mmol) of triethyl-
silane, and the mixture was stirred for 48 h. The reaction was
quenched with 5 mL of saturated aqueous sodium chloride
solution and extracted with ether (3 × 15 mL). The combined
organic extracts were washed with water (15 mL) and dried
(MgSO4), and the solvent was removed in vacuo. Purification
(()-tr a n s-N-(6,7-Dim et h oxy-1-p h en yl-1,2,3,4-t et r a h y-
d r on a p h th a len -2-yl)-N-(p-tolylsu lfon yl)glycin e, Meth yl
Ester (12b). Ester 12b was obtained in 79.7% yield from 11b,
as described for 12a , and recrystallized from hexane-ethyl

2146 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14
Negash et al.
of the crude product by centrifugal thin-layer chromatography
on a silica rotor using hexane-ethyl acetate (3:1) as the
developing solvent afforded 208 mg (40%) of 14a : mp 160-
161 °C; CIMS (isobutane) M + 1 434; 1H NMR (500 MHz,
CDCl3) δ 7.16 (d, 2, ArH, J ) 8.3 Hz), 7.10 (d, 1, ArH, J ) 8.4
Hz), 7.01-7.05 (m, 1, ArH), 6.95-7.0 (m, 2, ArH), 6.9 (t, 1,
ArH, J ) 7.3 Hz), 6.77 (dd, 1, ArH, J ) 2.3, 8.5 Hz), 6.61 (m,
2, ArH), 4.39 (d, 1, Ar2CH, J ) 11.6 Hz), 4.08-4.15 (m, 1,
ArCCHN), 3.93 (td, 1, CHN, J ) 2.4, 11.8 Hz), 3.67 (s, 3,
OCH3), 3.58-3.65 (m, 1, ArCCHN), 3.17-3.24 (m, 1, ArCHCN),
3.04-3.12 (m, 1, ArCH), 2.79-2.90 (m, 2, ArCH, ArCHCN),
2.35 (s, 3, ArCH3), 2.23-2.28 (m, 1, CHCN), 2.07-2.15 (m, 1,
CHCN). Anal. (C26H27NO3S) C, H, N.
7.3 Hz), 7.04-7.09 (m, 2, ArH), 6.98 (t, 1, ArH, J ) 7.5 Hz),
6.75 (dd, 1, ArH, J ) 2.7, 8.3 Hz), 6.54 (s, 1, ArH), 6.36 (d, 1,
ArH, J ) 7.6 Hz), 4.8 (d, 1, ArCH, J ) 7.0 Hz), 3.7 (s, 3, OCH3),
3.62-3.68 (m, 1, ArCCHN), 3.20-3.25 (m, 1, ArCCHN), 2.8-
2.88 (m, 2, ArCH2CN), 2.57-2.72 (m, 2, CHN, ArCH), 2.49-
2.55 (m, 4, NCH3, ArCH), 1.98-2.03 (m, 1, CHCN), 1.64-1.72
(m, 1, CHCN); HRCIMS calcd for C20H23NO 294.1858 (M +
H), found 294.1843.
(()-tr a n s-6,6a,7,8,9,13b-Hexah ydr o-7-m eth yl-5H-ben zo-
[d ]n a p th [2,1-b]a zep in -2-ol (5a ). To a solution of the free
base 16a (124 mg, 0.42 mmol) in dichloromethane (3 mL) was
added BBr3 (0.12 mL, 1.26 mmol) dropwise at -78 °C. The
reaction mixture was raised to room temperature over a period
of 2 h and with stirring continued for an additional 5 h. The
reaction mixture was then cooled to -78 °C, decomposed by
the addition of methanol (3 mL), and concentrated in vacuo.
The process of addition of methanol and evaporation was
repeated trice. The crude hydrobromide salt was suspended
in 5 mL of warm water, and the mixture was adjusted to pH
8 by dropwise addition of dilute sodium bicarbonate solution.
The reaction mixture was extracted with chloroform (3 × 3
mL). The combined organic extracts were washed with water
(2 × 3 mL) and dried (MgSO4), and the solvent was removed
in vacuo to give 108 mg (92%) of the free base 5a which was
recrystallized from acetonitrile: mp 210-212 °C; CIMS (isobu-
tane) M + 1 280; 1H NMR (CDCl3, free base) δ 7.12 (d, 1, ArH,
J ) 7.3 Hz), 7.02-7.08 (m, 2, ArH), 6.98 (t, 1, ArH, J ) 7.2
Hz), 6.7 9 (dd, 1, ArH, J ) 2.5, 8.2 Hz), 6.44 (s, 1, ArH), 6.37
(d, 1, ArH, J ) 7.6 Hz), 4.7 (d, 1, Ar2CH, J ) 7.1 Hz), 3.6 (t, 1,
ArCCHN, J ) 13.4 Hz), 3.2-3.26 (m, 1, ArCCHN), 2.66-2.8
(m, 3, ArCH2CN, CHN), 2.55-2.62 (m, 2, ArCH2), 2.5 (s, 3,
NCH3), 2.0-2.06 (m, 1, CHCN), 1.6-1.69 (m, 1, CHCN). Anal.
(HCl salt; C19H22NOCl‚0.25H2O) C, H, N.
(()-tr a n s-2,3-Dim et h oxy-7-(p -t olylsu lfon yl)-6,6a ,7,8,
9,13b-h exah ydr o-5H-ben zo[d]n aph th [2,1-b]azepin e (14b).
Amorphous 14b was obtained (62% yield) from 13b as de-
1
scribed for 14a : CIMS (isobutane) M + 1 464; H NMR (500
MHz, CDCl3) 7.04 (d, 2, ArH, J ) 8.2 Hz), 7.01 (t, 1, ArH, J )
7.4 Hz), 6.59 (d, 3, ArH, J ) 7.9 Hz), 6.58 (t, 1, ArH, J ) 7.4
Hz), 6.53 (s, 1, ArH), 6.52 (d, 1, ArH, J ) 7.42 Hz), 6.51 (s, 1,
ArH), 4.36 (d, 1, Ar2CH, J ) 11.69 Hz), 4.08-4.15 (m, 1,
ArCCHN), 3.88-3.96 (m, 4, CHN, OCH3), 3.59-3.7 (m, 4,
OCH3, ArCCHN), 2.78-2.87 (m, 2, ArCHCN, ArCH), 2.35 (s,
3, ArCH3), 2.23-2.28 (m, 1, CHCN), 2.08-2.16 (m, 1, CHCN).
(()-tr a n s-6,6a ,7,8,9,13b-Hexa h yd r o-2-m eth oxy-5H-ben -
zo[d ]n a p th [2,1-b]a zep in e (15a ). A solution of 262 mg (0.6
mmol) of 14a was suspended in 5 mL of xylene, and 0.67 mL
(2.23 mmol) of a 65+ wt % solution of sodium bis(2-methoxy-
ethoxy)aluminum hydride (Red-Al) in toluene was added. The
resulting mixture was heated at reflux for 1 h and cooled, and
5 mL of 15% sodium hydroxide was added. The mixture was
partitioned between water and ether, and the organic layer
was dried (MgSO4) and evaporated. Purification by centrifugal
thin-layer chromatography on a silica rotor, using hexane-
ethyl acetate (1:1) in an ammonia atmosphere, afforded 128
mg (76%) of the amine 15a . The hydrochloride salt of 15a was
recrystallized from methanol-ether: mp 270 °C dec; CIMS
(()-tr a n s-6,6a ,7,8,9,13b-Hexa h yd r o-5H-ben zo[d ]n a p th -
[2,1-b]a zep in e-2,3-d iol Hyd r obr om id e (5b). To a solution
of the free base 15b (20 mg, 0.065 mmol) in dichloromethane
(2 mL) was added BBr3 (0.03 mL, 0.26 mmol) dropwise at -78
°C. The crude hydrobromide salt was isolated as described
for 19 and recrystallized from ethanol-ether to give 17 mg
(71%) of the pure salt: mp 250 °C dec.; CIMS (isobutane) M
1
(isobutane) M + 1 280; H NMR (CDCl3, free base) δ 7.14 (d,
1, ArH, J ) 7.5 Hz), 7.05-7.1 (m, 2, ArH), 7.0 (t, 1, ArH, J )
7.0 Hz), 6.73 (dd, 1, ArH, J ) 3.0, 8.5 Hz), 6.55 (d, 1, ArH, J
) 7.5 Hz), 4.48 (d, 1, Ar2CH, J ) 7.5 Hz), 3.68 (s, 3, OCH3),
3.32-3.4 (m, 2, ArCCH2N), 2.78-2.84 (m, 2, ArCH2CN), 2.64-
2.73 (m, 3, ArCH2, CHN), 1.78-1.92 (m, 1, CHCN), 1.8 (b s, 1,
NH), 1.56-1.64 (m, 1, CHCN). Anal. (C19H22NOCl) C, H, N.
(()-tr a n s-6,6a ,7,8,9,13b-Hexa h yd r o-2,3-d im eth oxy-5H-
ben zo[d ]n a p th [2,1-b]a zep in e (15b). A solution of 55 mg
(0.12 mmol) of 14b was suspended in 1 mL of xylene, and 0.13
mL (0.45 mmol) of a 65+ wt % solution of sodium bis(2-
methoxyethoxy)aluminum hydride (Red-Al) in toluene was
added. The product was isolated (25 mg, 67%) as described
for 15a . The hydrochloride salt of 15b was recrystallized from
methanol-ether: mp 277-279 °C; CIMS (isobutane) M + 1
310; 1H NMR (CDCl3, free base) δ 7.16 (d, 1, ArH, J ) 7.0
Hz), 7.1 (t, 1, ArH, J ) 7.2 Hz), 7.02 (t, 1, ArH, J ) 7.6 Hz),
6.65 (s, 1, ArH), 6.0 (d, 1, ArH, J ) 7.6 Hz), 6.48 (s, 1, ArH),
4.86 (d, 1, Ar2CH, J ) 7.4 Hz), 3.58 (s, 3, OCH3), 3.54 (s, 3,
OCH3), 3.06-3.08 (m, 2, ArCCH2N), 2.56-2.57 (m, 2, ArCH2-
CN), 2.52-2.55 (m, 3, ArCH2, CHN), 1.75-1.83 (m, 1, CHCN),
1.55 (b s, 1, NH), 1.52-1.54 (m, 1, CHCN); HRCIMS calcd for
C20H23NO2 310.1807 (M + H), found 310.1807.
1
+ 1 282; H NMR (CD3OD, HBr salt) δ 7.26 (d, 2, ArH, J )
7.1 Hz), 7.18 (t, 1, ArH, J ) 7.4 Hz), 7.13 (t, 1, ArH, J ) 7.6
Hz), 6.66 (d, 1, ArH, J ) 8.0Hz), 6.63 (s, 1, ArH), 6.37 (s, 1,
ArH), 4.67 (d, 1, Ar2CH, J ) 8.2 Hz), 3.67-3.73 (m, 1H), 3.18-
3.245 (m, 2H), 3.0-3.1 (m, 2H), 2.7 (dd, 2H, J ) 5.7, 2.9 Hz),
3.16-2.23 (m, 1, CHCN), 1.73-1.82 (m, 1, CHCN); HRCIMS
calcd for free base C18H19NO2 282.1494 (M + H), found
282.1452.
(()-tr a n s-6,6a ,7,8,9,13b-Hexa h yd r o-3-iod o-2-m eth oxy-
7-m eth yl-5H-ben zo[d ]n a p th [2,1-b]a zep in e (17). To a solu-
tion of 16a (160 mg, 0.55 mmol) in ethanol (4 mL) was added
silver sulfate (342 mg, 1.1 mmol) followed by iodine (279 mg,
1.10 mmol), and the mixture was stirred at room temperature
for 24 h. The resulting yellow solid was removed by filtration,
and the filtrate was evaporated to dryness under reduced
pressure. The residue was dissolved in dichloromethane and
washed with 5% aqueous sodium hydroxide solution (3 mL),
followed by water (5 mL). After separation, the organic layer
was dried (MgSO4) and evaporated in vacuo. Purification of
the residue by centrifugal thin-layer chromatography on a
silica rotor, eluting with 20% ethyl acetate in hexane, afforded
138 mg (60%) of the free base 17 which was recrystallized from
acetonitrile: mp 159-161 °C; CIMS (isobutane) M + 1 420;
1H NMR (500 MHz, CDCl3) δ 7.6 (s, 1, ArH), 7.14 (d, 1, ArH,
J ) 7.4 Hz), 7.08 (t, 1, ArH, J ) 7.4 Hz), 7.0 (t, 1, ArH, J )
7.6 Hz), 6.46 (s, 1, ArH), 6.35 (d, 1, ArH, J ) 7.6 Hz), 4.76 (d,
1, Ar2CH, J ) 7.1 Hz), 3.72 (s, 3, OCH3), 3.65 (t, 1, ArCCH, J
) 13.4 Hz), 3.22 (dd, 1, ArCCH, J ) 5.6, 13.5 Hz), 2.76-2.85
(m, 2, ArCH2CN), 2.54-2.68 (m, 3, CHN, ArCH2), 2.52 (s, 3,
NCH3), 1.98-2.04 (m, 1, CHCN), 1.58-1.68 (m, 1, CHCN).
Anal. (C20H22NOI‚0.25H2O) C, H, N.
(()-tr a n s-6,6a,7,8,9,13b-Hexah ydr o-7-m eth yl-2-m eth oxy-
5H-ben zo[d ]n a p th [2,1-b]a zep in e (16a ). A solution of 144
mg (0.46 mmol) of amine hydrochloride 15a was mixed with
0.23 mL (2.86 mmol) of 37% formalin solution and 118 mg (1.78
mmol) of 97% sodium cyanoborohydride in 8 mL of methanol,
and the mixture was stirred overnight at room temperature.
After removal of the volatiles in vacuo, the residue was
partitioned between 5% HCl and ether. The layers were
separated, the aqueous layer was washed once more with
ether, and the organic fractions were discarded. The aqueous
layer was made basic with concentrated ammonium hydroxide,
and the alkylated amine was then extracted into 3 × 40 mL
of dichloromethane, which was dried (MgSO4) and then
filtered. The solvent was removed in vacuo to give 129 mg
(95%) of the free base 16a as a colorless oil: CIMS (isobutane)
M + 1 294; 1H NMR (CDCl3, free base) δ 7.13 (d, 1, ArH, J )
(()-tr a n s-6,6a ,7,8,9,13b -H exa h yd r o-3-iod o-7-m et h yl-
5H-ben zo[d ]n a p th [2,1-b]a zep in -2-ol Hyd r och lor id e (5c).
To a solution of the free base 17 (50 mg, 0.12 mmol) in
dichloromethane (2 mL) was added BBr3 (0.03 mL, 0.36 mmol)
dropwise at -78 °C. The free base 5c was isolated in 70%

Definition of the D1 Dopamine Receptor Pharmacophore
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 14 2147
(6) Berger, J . G.; Chang, W. K.; Clader, J . W.; Hou, D.; Chipkin, R.
E.; McPhail, A. T. Synthesis and receptor affinities of some
conformationally restricted analogues of the dopamine D1 selec-
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yield as described for 5a . Following acidification, the hydro-
chloride salt was recrystallized from methanol-ethyl ac-
etate: mp 233-235 °C; CIMS (isobutane) M + 1 406; 1H NMR
(free base, CDCl3) δ 7.48 (s, 1, ArH), 7.08 (d, 1, ArH, J ) 7.0
Hz), 7.04 (t, 1, ArH, J ) 7.4 Hz), 6.96 (t, 1, ArH, J ) 7.5 Hz),
6.47 (s, 1, ArH), 6.32 (d, 1, ArH, J ) 7.7 Hz), 4.48 (d, 1, Ar2-
CH, J ) 6.9 Hz), 3.42 (t, 1, ArCCHN, J ) 13.6 Hz), 3.22-3.3
(m, 1, ArCCHN), 2.5-2.64 (m, 5, ArCH2CN, CHN, ArCH2),
2.48 (s, 3, NCH3), 2.02-2.08 (m, 1, CHCN), 1.53-1.62 (m, 1,
CHCN). Anal. (C19H21INOCl) C, H, N.
Dop a m in e D1 a n d D2 Recep tor Affin ity. Rat striatum
was homogenized by seven manual strokes in a Wheaton
Teflon glass homogenizer in ice-cold 50 mM HEPES buffer
with 4.0 mM MgCl2 at pH 7.4. Tissue was centrifuged at
27000g for 10 min, the supernatant discarded, and the pellet
homogenized (five strokes) and resuspended in ice-cold buffer
and centrifuged again. The final pellet was suspended at a
concentration of approximately 2 mg wet weight/mL.
The assay buffer was 50 mM HEPES with 4 mM MgCl2 (pH
7.4). Assay tubes containing a final volume of 1.0 mL were
incubated at 37 °C for 15 min. Nonspecific binding of [3H]-
SCH 23390 was defined by adding 1 µM unlabeled SCH 23390.
Incubations were filtered through glass-fiber filter mats with
a 15 mL of ice-cold buffer wash using a Skatron cell harvester.
Filters were allowed to dry, and 3.0 mL of Scintiverse E
(Fischer Scientific) was added. After 30 min of shaking,
radioactivity was counted on an LKB Betarack liquid scintil-
laton counter. Tissue-protein levels were estimated using the
the Bradford dye-binding method.
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The binding procedure and protein analysis were identical
with that described above except that [3H]spiperone was used
as the radioligand. Nonspecific binding of [3H]spiperone was
defined by adding unlabeled 1 µM chlorpromazine. Ketanserin
tartrate (50 nM) was added to prevent binding of [3H]spiperone
to serotonin receptors.
With both receptors, the resulting concentration curves were
analyzed by nonlinear regression using the algorithms in
Prism (GraphPad Inc.). All of these data are expressed as K0.5
,
in which the experimental IC50 is corrected for the radioligand
concentration using the following formula: K0.5 ) IC50/(1 +
L*/KD*) where L* is the experimental radioligand concentra-
tion and KD* is the KD of the radioligand. In cases where the
Hill slope (nH) ) 1, K0.5 ) KD. Expressing the data in this
form when nH < 1 obviates the need to pick a more complex
model (e.g., two vs three site).
(20) Nordlander, J . E.; Payne, M. J .; Njoroge, F. G.; Balk, M. A.;
Laikos, G. D.; Vishwanath, V. M. Friedel-Crafts acylation with
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Ack n ow led gm en t. This work was supported by
PHS Grants MH42705 and MH40537, Center Grants
HD03310 and MH33127, and Training Grant GM07040.
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