Further characterization of structural requirements for ligands at the dopamine D2 and D3 receptor: Exploring the thiophene moiety

Article abstract of DOI:10.1021/jm001015a

The present study describes the synthesis and in vitro pharmacology of a novel series of dopaminergic agents in which the classical phenylethylamine pharmacophore is replaced by a thienylethylamine moiety. In general, the novel compounds showed a moderate

Full text of DOI:10.1021/jm001015a

3022
J . Med. Chem. 2002, 45, 3022-3031
F u r th er Ch a r a cter iza tion of Str u ctu r a l Requ ir em en ts for Liga n d s a t th e
Dop a m in e D2 a n d D3 Recep tor : Exp lor in g th e Th iop h en e Moiety
Durk Dijkstra,*,† Nienke Rodenhuis,† Erik S. Vermeulen,† Thomas A. Pugsley,‡ Lawrence D. Wise,‡ and
Håkan V. Wikstro¨m†
Department of Medicinal Chemistry, University of Groningen, Antonius Deusinglaan 1, NL-9713 AV Groningen,
The Netherlands, and CNS Chemistry and Pharmacology, Pfizer Global Research and Development, Ann Arbor Laboratories,
2800 Plymouth Road, Ann Arbor, Michigan 48105
Received J une 26, 2000
The present study describes the synthesis and in vitro pharmacology of a novel series of
dopaminergic agents in which the classical phenylethylamine pharmacophore is replaced by a
thienylethylamine moiety. In general, the novel compounds showed a moderate affinity for
the dopamine (DA) D2 and D3 receptors. When the thienylethylamine moiety is fixed in a rigid
system, the affinity for the DA receptor is significantly increased. However, in the tricyclic
hexahydrothianaphthoxazine structure, the affinity for the DA receptors is diminished.
In tr od u ction
quinolines, using a pharmacological in vivo model
measuring DA D2 activity, that one of the N-alkyl
binding sites can only tolerate N-substituents equal to
an n-propyl. Seiler and Markstein10 conclude that this
space-limited accessory binding site, which they call the
“small N-alkyl binding site”, exists in both main groups
of the DA receptors.
For a more extensive exploitation of this theory, we
synthesized some derivatives of the potent DA D2/D3
agonist PHNO 1a .11,12 According to the Wikstro¨m/Seiler
modification of McDermed’s model, N-substituents larger
than n-propyl should produce compounds which are
inactive at the DA D2/D3 receptors, while the steric
requirements for an R group on the 2-position should
be less critical.
The in vitro pharmacology data of the naphthoxazines
(Table 1) confirmed that an N-substituent should not
be larger than an n-propyl, and that there is more
structural freedom for a 2-substituent. However, a
thienylethyl substituent on the nitrogen (1c) gave a
compound with a significantly higher affinity for the DA
D3 receptor than for the phenylethyl analogue 1b. We
speculated about the reason for the increased affinity
for the D3 receptor and hypothesized that the dopa-
minergic pharmacophore of compound 1c is the thien-
ylethylamine moiety (pharmacophore 2, Chart 1) and
not the 3-OH-phenylethylamine moiety (pharmacophore
1, Chart 1). The possibility of an interaction of the
thienylethylamine moiety with additional parts of the
receptor cannot be ruled out entirely. To test the
hypothesis, the thienylethylamines 3 and 4 were syn-
thesized and tested in vitro (Chart 2).
It has been known for a long time that the 2-amino-
tetralin (2-amino-1,2,3,4-tetrahydronaphthalene) struc-
ture is pharmacologically valuable. The 2-aminotetralin
system has proven to be a useful structural base for
dopaminergic, serotonergic, and adrenergic ligands, as
well as for compounds that interact with melatonin
receptors.13,14
Recent advances in molecular biology have estab-
lished the existence of two families of dopamine recep-
tors: a D2-group comprising D2, D3, and D4 receptors
and a D1-group incorporating D1 and D5 receptors.1,2
Dopamine (DA) is a major neurotransmitter in the
central nervous system. Receptors for this catechola-
mine are of considerable interest, as they are the
principal target for drugs employed in the treatment of
neuropsychiatric disorders, such as schizophrenia, drug
dependence, and Parkinson’s disease. For that reason,
dopaminergic ligands have attracted considerable at-
tention.3-5
DA receptor agonist activities can be found in several
classes of compounds, including 2-phenylethylamines,
aporphines, 2-aminotetralins, naphthoxazines, and er-
goline derivatives. Dopamine, and most of the known
DA receptor agonists, bind with a higher affinity to the
DA D3 than to the DA D2 receptor. Due to the close
homology between the DA D2 and D3 receptors, espe-
cially in the TM domains (∼80%), it is difficult to predict
DA D2 versus DA D3 receptor selectivity based on
receptor models. Malmberg et al.6 suggested that the
observed DA D3 selectivity may not be due to a single
specific interaction but, rather, to a small difference in
conformation between the D3 and D2 receptors.
McDermed et al.7 elegantly rationalized the hetero-
chirality of the potent DA receptor agonists by suggest-
ing a model in which different faces of the compound
would interact with a putative three-point pharmaco-
phore. An attractive feature of this model is that it
allows a superposition of the pharmacophoric elements
of several DA receptor agonists, such as the nitrogens,
nitrogen lone pairs, oxygens, and aromatic rings. In
addition, the presence of two lipophilic sites which bind
the N-alkyl groups has been postulated.8 Wikstro¨m et
al.9 have shown with a series of octahydrobenzo[f]-
* To whom correspondence should be addressed. Tel: +31-50-
3633310. Fax: +31-50-3636908. E-mail: D.Dijkstra@farm.rug.nl.
† University of Groningen.
Some of these compounds have been studied by
several research groups to elucidate their SAR for DA
receptors.8-10,15-19 Initially, these studies identified S-
‡ CNS Chemistry and Pharmacology, Pfizer Global Research and
Development.
10.1021/jm001015a CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/05/2002

Requirements for Ligands at the Dopamine Receptor
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3023
Ch a r t 1. Structures of Some Dopaminergic Ligands
Ch a r t 4. Chemical Structures of Novel Thiophene
Analogues of 2-Aminotetralins and
Hexahydronaphthoxazines
Ch a r t 2. Chemical Structures of Some
Thienylethylamines
Sch em e 1a
Ch a r t 3. Chemical Structures of Some
2-Aminotetralins and Analogues
a
Reagents: (a) C6H5CH2CH2Br, K2CO3, DMF or 2-thienyl acetic
acid, (CH3)3N‚BH3, xylene; (b) BBr3, CH2Cl2.
for potent dopaminergic activity was presented by
Ande´n et al.,22 who showed that the aminothiazolaze-
pine derivative BHT920 (8) is a DA autoreceptor ago-
nist, as well as an R2-adrenoceptor agonist. Pramipexole
(9), a benzothiazole analogue of the 2-aminotetralins,
was found to be a potent DA receptor ligand with both
DA D2 and D3 receptor stimulating properties (Chart
3). It is presently on the market for the treatment of
Parkinson’s disease.23-25
Since it was found that compounds with a thienyl-
ethylamine moiety have an affinity for the dopamine
receptor, we were interested in the effect of the replace-
ment of the phenol in 2-aminotetralins and hexahy-
dronaphthoxazines with a thiophene moiety. Therefore,
thiophene analogues of the 2-aminotetralins and hexahy-
dronaphthoxazines, 10-15, were synthesized (Chart 4).
All the compounds synthesized were tested in vitro for
their affinity at the DA D2L and D3 receptors. The
derivatives with interesting properties were further
investigated for their in vivo dopaminergic activity and
bioavailability using the microdialysis technique in
freely moving rats.26
(-)-5-hydroxy-2-(N,N-di-n-propylamino)tetralin (S-(-)-
5-OH-DPAT or S-(-)-5) as the most potent monohydroxy
2-aminotetralin.8,10,15 Later, S-(-)-5-hydroxy-2-(N-n-pro-
pyl-N-2-thienylethylamino)tetralin (S-(-)-N-0437 or S-
(-)-7) was found to be an even more potent DA receptor
agonist.19 Moreover, R-(+)-7-hydroxy-2-(N,N-di-n-pro-
pylamino)tetralin (R-(+)-7-OH-DPAT or R-(+)-6) was
later shown to have a preference for the DA D3 receptor
subtype (Chart 3).20,21
Ch em istr y
The clinical utility of catechol- and phenol-containing
drugs has been limited due to their low oral bioavail-
ability and short duration of action. The catechol and
phenol rings provide optimal sites for glucuronidation.
Thus, for many years, emphasis has been focused on
the identification of bioisosteric replacements of cat-
echols and phenols. The idea that neither catecholic nor
phenolic hydroxyl groups are an absolute requirement
The trans-N-arylalkyl substituted hexahydronaph-
thoxazines 1b and 1c were synthesized from the trans-
9-methoxy secondary amine 16 either by N-alkylation
with the appropriate arylethyl halide or by reductive
alkylation.11 The cleavage of the methoxy ethers to
phenols was achieved with BBr3 under N2 (Scheme 1).
The synthesis of 2-phenyl-N-n-propylnaphthoxazine
is outlined in Scheme 2. The racemic trans-amino

3024 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Dijkstra et al.
Sch em e 2a
a
Reagents: (a) PhCHClCOCl, NaOH, CH2Cl2; (b) NaOH, 2-propanol; (c) BH3‚Me2S, THF; (d) BBr3, CH2Cl2.
Sch em e 3a
Sch em e 4a
a
Reagents: (a) C3H7NH2, CH2Cl2; (b) BH3‚Me2S, THF; (c) 2-
or 3-thienylacetyl chloride, CH2Cl2, Et3N.
alcohol 18 was acylated with 2-chloro-2-phenylacetyl
chloride to afford a mixture of diastereomeric trans-
amido alcohols. Cyclization of the amido alcohol 19 was
achieved with NaOH in 2-propanol, affording the mix-
ture of trans-lactams 20a and 20b with the 2-phenyl
ring in the equatorial or axial position.
The 2-(axial)phenyl trans-lactam and the 2-(equato-
rial)phenyl trans-lactam could be separated by column
chromatography. NOESY experiments show that the
fast-eluting compound has an interaction between the
protons on C10b and C15/C19; hence, this is the
compound with the phenyl ring in the axial position.
The slow-eluting compound shows an interaction be-
tween the protons on C10b and C2, indicating that the
compound has the phenyl ring in the equatorial position.
The 2-equatorial-phenyl isomer was used for the next
reaction. After reduction of the amide with the BH3‚
Me2S complex, the final step was demethylation, which
was achieved by applying BBr3 to give the final product
2.
The thienylethylamines 3 and 4 were synthesized
according to Scheme 3. The secondary amine 23 was
acylated with 2- or 3-thienylacetyl chloride. The 1H- and
13C-NMR spectra of the amides 24 and 25 showed
nonequivalency for the aliphatic hydrogen and carbon
atoms, indicating a partial double-bond character. The
resulting amides were reduced with the BH3‚Me2S
complex.
The synthesis of the tetrahydrobenzo[b]thiophenes is
outlined in Scheme 4. A Grignard reaction of 26 with
ClMgCH2SiMe3 followed by quaternization with methyl
iodide gave the 3-(trimethylammoniummethyl)-2-(tri-
a
Reagents: (a) ClMgCH2SiMe3, Ni(PPh3)2Cl2, Et2O; (b) CH3I,
CH3CN; (c) CH2dCHCO2CH3, TBAF, CH3CN; (d) NaOH; (e) (1)
DPPA, Et3N, dioxane; (2) HCl, dioxane, 120 °C; (f) C3H7I, K2CO3,
DMF; (g) SiO2 column chromatography, EtOAc:hexane ) 1:9.
methylsilylmethyl)thiophene 28.27 Treatment of 28 with
n-tetrabutylammonium fluoride (TBAF) led to the for-
mation of 2,3-dimethylene-2,3-dihydrothiophene. This
unstable intermediate was captured in a Diels-Alder
[4 + 2] cycloaddition reaction with methyl acrylate as
the dienophile. Hydrolysis of the mixture of esters gave
the carboxylic acids 30a and 30b in good yield. A
Curtius rearrangement gave the mixture of the amines
31a and 31b.27 Only after conversion into the tertiary
amines of 10 and 11 was it possible to separate the
mixture of regioisomers on a SiO2 column.
The methyleneaminotetrahydrobenzo[b]thiophenes 12
and 13 were synthesized from the corresponding car-
boxylic acids 30a and 30b in three steps by standard
chemistry (Scheme 5). Again, the two isomers could be
separated on a SiO2 column after their conversion to
the tertiary amines.
The hexahydrothianaphthoxazines 14 and 15 were
synthesized from the commercially available ketone 34,
which was readily converted into the tosyloxime 36
(Scheme 6). Neber rearrangement of 36 with potassium
tert-butoxide afforded the desired amino ketone 37. The
amino ketone 37 was readily acylated with chloroacetyl
chloride. Reduction of the keto-chloroacetamide 38 with
sodium borohydride gave only the trans isomer. The
proton on C1 gave a doublet at δ 4.6 ppm with a
coupling constant of 7.2 Hz, indicating a diaxial cou-

Requirements for Ligands at the Dopamine Receptor
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3025
Sch em e 5a
Ta ble 1. Receptor Binding Data of Various Dopaminergic
Compounds
Ki (nM)a
compound no.
D2L [3H]N-0437
D3 [3H]spiperone
(+)-PHNO ((+)-1a )
6.24
>3676
3676
375
1080
439
0.21
1566
83
(()-1b
(()-1c
(()-2
3
4
10
12
117
108
28
27
11
12
13
14
20
40
60
3107b
2037
>4780b
630b
14
247
3000
240
0.54
0.57
4.0
15
(-)-5-OH-DPAT (5)5
(+)-7-OH-DPAT (6)5
(()-N-0437 (7)5
a
Reagents: (a) oxalyl chloride, CH2Cl2; (b) (C3H7)2NH, Et3N,
34
0.06
CH2Cl2; (c) LiALH4, THF; (d) SiO2 column chromatography,
CH2Cl2:MeOH ) 20:1.
a
Ki values are the means of two to six separate experiments,
the results of which did not vary by more than 25%. [3H]NPA
b
pling. The cyclization of the alcohol-chloroacetamide 39
by means of 50% NaOH in 2-propanol at room temper-
ature gave satisfactory yields of the lactam 40, which
was then reduced with LiAlH4 to the oxazine 14.
Alkylation of the amine 14 with propyl iodide in DMF
afforded the tertiary amine 15 in good yield.
was used as a radiolabeled ligand.
dopaminergic D3 properties to this compound. Several
studies have shown that some transmembrane seg-
ments play an important role in the formation of the
binding pocket of the DA receptors. This leads to the
assumption that the protonated nitrogen of ligands
interacts with Asp 114 (D2) or Asp 110 (D3) in TM 3
through a reinforced ionic bond (for review see ref 1).
In the hydroxylated 2-aminotetralins and OHB[f]Qs, an
additional hydrogen bond is formed from the phenolic
hydrogen of the ligands to either Ser 193 (D2) or Ser
192 (D3) in TM 5.6 If a thiophene ring utilizes the same
interaction points as the phenol, it may be speculated
that the sulfur atom in the thienylethyl substituent
forms a hydrogen bond with the hydroxyl moiety of a
Ser residue. Sulfur can only act as a hydrogen-bond
acceptor, and consequently, this weaker interaction may
provide an explanation for the lower affinity for the DA
D3 receptor of compound 1c compared to that of com-
pound 1a .28,29 An alternative explanation for the dimin-
ished affinity is the utilization of other interaction points
of the receptor.
Resu lts a n d Discu ssion
The structural requirements for the N-substituents
of dopaminergic 7- and 9-hydroxylated octahydrobenzo-
[f]quinolines (OHB[f]Qs) and related compounds have
been described previously.9 In vivo biochemical and
behavioral data demonstrated that the n-propyl group
is optimal for dopaminergic activity. Larger N-substit-
uents (e.g., n-butyl) for the 9-hydroxy-OHB[f]Qs gave a
dramatic reduction in the potency of these compounds.
The Ki values shown in Table 1 for the N-substituted
9-hydroxy-hexahydronaphthoxazines (9-OH-HNO) 1b
and 2 are in full agreement with the models of Mc-
Dermed and Wikstro¨m.7,9 According to these models,
there is space available for a 2-substituent. Interest-
ingly, however, the DA D3 affinity of 1c (Ki ) 83 nM)
showed that this compound does not fit these receptor
models. This has led us to hypothesize that it is the
thienylethylamine moiety of 1c which confers the
The in vitro pharmacology of compounds 3 and 4
possessing only the thienylethylamine moieties (Table
Sch em e 6a
a
Reagents: (a) NH2OH‚HCl; (b) TsCl; (c) t-BuOK/EtOH; (d) HCl/H2O; (e) ClCH2COCl, NaOH, CH2Cl2; (f) NaBH4; (g) NaOH; (h) LiAlH4;
(i) C3H7I, DMF, K2CO3.

3026 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Dijkstra et al.
m (multiplet), and dd (double doublet). Chemical shifts are
given in δ units (ppm) and are relative to the solvent. Coupling
constants are given in hertz (Hz). The spectra recorded were
consistent with the proposed structures. IR spectra were
obtained on an ATI-Mattson spectrometer. Elemental analyses
were performed either by the Analytical Chemistry Section
at Parke Davis (Ann Arbor, MI) or by the Microanalytical
Department of the University of Groningen, and were within
(0.4% of the theoretical values, except where noted. All
chemicals used were commercially available (Aldrich or Acros)
and were used without further purification.
1) showed that these compounds possess low to moder-
ate affinity for the DA D3 receptor, but it confirmed our
assumption that a thienylethylamine moiety can act as
a nonoptimal pharmacophore at the DA D3 receptor.
The thiophene analogues of the 2-aminotetralins (10
and 11) have considerable affinity for the DA D2 and
D3 receptors, but it is significantly lower than that for
5-OH-DPAT (Table 1). As stated earlier, one reason
could be the less-tight hydrogen bonding of the sulfur
atom. The results of compounds 10 and 11 confirmed
the hypothesis that a thienylethylamine may act as a
pharmacophore; moreover, compared to the thienyleth-
ylamines (3, 4), the semirigid system increased the
affinity for the DA receptor. Apparently, the near
coplanar arrangement is favorable for higher DA agonist
activity. This is in line with the higher potency of the
hydroxylated 2-aminotetralin analogues compared to
that of the phenylethylamines.31,32 It is known from
literature that hydroxylated 2-aminotetralins and
hexahydronaphthoxazines are potent dopaminergic ago-
nists, but their oral bioavailability is very low due to
glucuronidation in the liver.30 The use of microdialysis
experiments in the rat allowed for the calculation of the
relative oral bioavailabilities of the compounds 10, 11,
and 5-OH-DPAT.26 These data show that, although the
affinities of the benzo[b]thiophenes (10 and 11) for the
DA receptors are lower compared to those of 5-OH-
DPAT, their relative oral bioavailability is higher.
Compounds 10 and 11 showed relative oral bioavail-
abilities of 10% and >10%, respectively. The reference
compound has a relative oral bioavailability of about
1%.26 Therefore, the benzo[b]thiophenes are interesting
lead compounds for further research.
tr a n s-9-Meth oxy-4-(2-p h en yleth yl)-2,3,4a ,5,6,10b-h exa -
h yd r o-4H-n a p h th [1,2b][1,4]oxa zin e (17a ). A solution of
trans-9-methoxy-2,3,4a,5,6,10b-hexahydro-4H-naphth[1,2b]-
[1,4]oxazine (16) (0.42 g, 1.91 mmol), K2CO3 (1.5 g, 10.85
mmol), and 2-phenylethylbromide (0.39 g, 2.10 mol) in 15 mL
of DMF was stirred for 15 h at 60 °C under an atmosphere of
nitrogen. The reaction mixture was allowed to cool to room
temperature, and then poured into water and extracted 3 times
with 30 mL of diethyl ether. The combined organic phases were
extracted several times with brine, dried over Na2SO4, and
filtered, and the solvent was removed under reduced pressure.
The residue was further purified by flash chromatography
(SiO2) using a mixture of CH2Cl2 and MeOH (25/1) as the
eluent. After evaporation of the solvent, the yield was 0.39 g
(63%) of 17a , which was converted to the HCl salt: mp 239-
241 °C; 1H-NMR (CD3OD, δ) 1.9-2.1 (m, 1H), 2.5-2.7 (m, 1H),
2.9-3.0 (m, 2H), 3.1-3.3 (m, 2H), 3.4-3.6 (m, 3H), 3.7-3.9
(m, 2H), 3.8 (s, 3H), 4.2-4.4 (m, 2H), 4.8 (d, 1H, J ) 9.3 Hz),
6.9-7.0 (m, 1H), 7.0-7.2 (m, 2H), 7.3-7.5 (m, 5H); 13C-NMR
(CD3OD, δ) 20.3, 24.7, 27.7, 49.7, 51.9, 53.3, 62.2, 62.7, 74.8,
108.4, 113.0, 124.7, 125.7, 127.4, 127.8, 133.4, 135.2, 156.9.
Anal. (C21H25NO2‚HCl) C, H, N.
tr a n s-9-Hyd r oxy-4-(2-p h en yleth yl)-2,3,4a ,5,6,10b-h exa -
h yd r o-4H-n a p h th [1,2b][1,4]oxa zin e (1b). To a cooled solu-
tion (-30 °C) of 17a ‚HCl (0.22 g, 0.61 mmol) in 30 mL of
dichloromethane was added a 1 M solution of BBr3 in CH2Cl2
under an atmosphere of nitrogen. The reaction mixture was
initially stirred for 1 h at this temperature, and then allowed
to rise to room temperature, after which the reaction mixture
was stirred for another 3 h. The reaction mixture was then
poured into water that had been made alkaline by the addition
of a solution of NaHCO3. The separated organic layer was
washed with brine, dried over Na2SO4, and filtered, and the
solvent was removed under reduced pressure. Conversion to
the HCl salt and recrystallization from acetonitrile yielded 0.12
g (51%) of 1b: mp of the free base 173-176 °C; 1H-NMR
(CDCl3, δ) 1.6-1.8 (m, 1H), 2.2-2.4 (m, 2H), 2.6-2.9 (m, 6H),
3.0-3.2 (m, 2H), 3.9-4.1 (m, 2H), 4.4 (d, 1H, J ) 9.7 Hz), 6.6-
6.8 (m, 1H), 6.9-7.0 (m, 2H), 7.2-7.4 (m, 5H); 13C-NMR
(CDCl3, δ) 22.5, 25.6, 30.3, 50.7, 53.4, 60.9, 65.4, 77.1, 110.4,
Compounds 12 and 13 were synthesized to enlarge
the distance between the nitrogen and sulfur atom.
Compound 12 had no affinity for the DA D2 receptor
and only a moderate affinity for the DA D3 receptor. The
distance between the sulfur and nitrogen atoms of
compounds 12 and 13 in an extended minimized con-
formation (using the computer program MacroModel)
is between 5.7 and 6.7 Å, depending on the conformation
of the methylene amino group. This distance is compa-
rable with the distance between the hydroxyl group and
the nitrogen atom in the 2-aminotetralins.
Although the distances between the sulfur and nitro-
gen atoms in the hexahydrothianaphthoxazines (14 and
15) are comparable with those in 5-(N-(di-n-propyl))-
amino-4,5,6,7-tetrahydrobenzo[b]thiophene 11, the in-
troduction of a morpholine ring gave a dramatic de-
crease in the DA D2 and D3 receptor affinity.
113.2, 124.7, 125.2, 127.0, 127.2, 127.8, 152.8. Anal. (C20H23
-
NO2‚2HCl) C, H, N.
tr a n s-9-Meth oxy-4-(2-th ien yleth yl)-2,3,4a ,5,6,10b-h exa -
h yd r o-4H-n a p h th [1,2b][1,4]oxa zin e (17b). To a solution of
trans-9-methoxy-2,3,4a,5,6,10b-hexahydro-4H-naphth[1,2b]-
[1,4]oxazine (16) (0.5 g, 2.3 mmol) and trimethylamine borane
complex (0.34 g, 4.6 mmol) in 30 mL of xylene was added
2-thienyl acetic acid (0.65 g, 4.5 mmol). The mixture was
heated under N2 and refluxed for 15 h. The mixture was
poured into water. The organic layer was separated, and the
aqueous layer was extracted with diethyl ether (2 × 25 mL).
The combined organic layer was washed with NaHCO3 solu-
tion and brine and dried over MgSO4. Evaporation of the
solvents yielded an oil which was converted to the HCl salt
and recrystallized from ethanol to yield 0.46 g (62.3%) of 17b:
mp 195.5-197 °C; 1H-NMR (CD3OD, δ) 2.5-2.8 (m, 1H), 3.1-
3.3 (m, 1H), 3.5-3.7 (m, 2H), 4.0-4.2 (m, 5H), 4.4-4.6 (m, 2H),
4.4 (s, 3H), 4.8-5.1 (m, 2H), 5.5 (d, 1H, J ) 9.5 Hz), 7.5-7.6
(m, 1H), 7.7-7.9 (m, 2H), 8.1 (d, 1H, J ) 3.7 Hz); 13C-NMR
(CD3OD, δ) 20.9, 22.7, 25.4, 52.4, 53.8, 63.1, 63.3, 75.4, 109.1,
113.6, 124.0, 125.3, 125.6, 126.4, 128.4, 133.9, 137.3, 157.6.
Anal. (C19H23NO2S‚HCl) C, H, N.
In conclusion, bioisosteric replacement of a phenol by
a thiophene moiety gave DA agonists with poorer
affinity than the corresponding 2-aminotetralins. This
loss in affinity is, however, partly compensated by a
higher oral bioavailability of the tetrahydrobenzo[b]-
thiophenes 10 and 11.
Exp er im en ta l Section
Ch em istr y. Melting points were determined in open glass
capillaries on an electrothermal digital melting-point ap-
1
paratus and are uncorrected. H- and 13C-NMR spectra were
recorded at 200 and 50.3 MHz, respectively, on a Varian
Gemini 200 spectrometer. The splitting patterns are desig-
nated as follows: s (singlet), d (doublet), t (triplet), q (quartet),

Requirements for Ligands at the Dopamine Receptor
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3027
tr a n s-9-Hyd r oxy-4-(2-th ien yleth yl)-2,3,4a ,5,6,10b-h exa -
h yd r o-4H-n a p h th [1,2b][1,4]oxa zin e (1c). Compound 1c was
prepared from the methoxy compound 17b by essentially the
same procedure as described for the preparation of 1b. The
yield was 65%. An analytical sample was recrystallized from
ethanol diethyl ether to provide white crystals: mp of the free
oil. The amine was converted to the HCl salt: mp 209-210
°C; 1H-NMR (CDCl3, δ) 0.9 (t, 3H, J ) 7.3 Hz), 1.5-1.7 (m,
3H), 2.3-2.4 (m, 4H), 2.8-2.9 (m, 3H), 3.1 (dd, 1H, J ) 11.7
Hz), 3.8 (s, 3H), 4.6 (d, 1H, J ) 9.03 Hz), 4.9 (dd, 1H, J ) 10.5
Hz), 6.7-6.8 (m, 1H), 7.0 (d, 1H, J ) 8.3 Hz), 7.2 (m, 1H), 7.3-
7.5 (m, 5H); 13C-NMR (CDCl3, δ) 10.5, 17.0, 22.8, 25.8, 53.6,
53.9, 58.1, 60.3, 76.7, 77.5, 108.6, 112.2, 124.6, 125.6, 126.1,
126.8, 127.5, 136.0, 139.2, 156.36. Anal. (C22H27NO2‚HCl) C,
H, N.
1
base 173-175 °C and of the HCl salt 231-234 °C; H-NMR
(CD3OD, δ) 1.8-2.0 (m, 1H), 2.5-2.6 (m, 1H), 2.8-3.0 (m, 2H),
3.3-3.5 (m, 5H), 3.7-3.8 (m, 2H), 4.1-4.4 (m, 2H), 4.7 (d, 1H,
J ) 9.8 Hz), 6.6-6.7 (m, 1H), 6.9-7.1 (m, 4H), 7.3 (d, 1H, J )
4.9 Hz); 13C-NMR (CDCl3, δ) 20.3, 22.0, 24.6, 51.9, 54.0, 62.4,
62.8, 74.9, 109.9, 113.8, 122.9, 123.1, 124.7, 125.5, 127.3, 132.7,
136.1, 154.3. Anal. (C18H21NO2S‚HCl‚1/4H2O) C, H, N.
tr a n s-9-Hyd r oxy-2-p h en yl-4-N-n -p r op yl-2,3,4a ,5,6,10b-
h exa h yd r o-4H-n a p h th [1,2b][1,4]oxa zin e (2). The phenol 2
was prepared from the methoxy compound 21 by essentially
the same procedure as described for the preparation of 1b from
17a . The yield was 60%. An analytical sample was recrystal-
lized from acetonitrile to provide white crystals: mp 202-204
tr a n s-9-Meth oxy-2-p h en yl-4-N-n -p r op yl-2,3,4a ,5,6-tet-
r a h yd r o-4H-n a p h th [1,2b][1,4]oxa zin -3-on e (20a a n d 20b).
To a solution of 18 (1.14 g, 4.8 mmol) in 70 mL of dichlo-
romethane was added NaOH (1.0 g) dissolved in 10 mL of
water. The compound 2-chloro-2-phenyl acetyl chloride (1.0 g,
5.3 mmol) was dissolved in 10 mL of dichloromethane and
slowly added. The reaction mixture was stirred at room
temperature for 2 h. The mixture was then poured into 60 mL
of water. The two layers were separated, and the aqueous layer
was extracted with dichloromethane. The combined organic
extracts were washed with water and dried over Na2SO4. After
filtration, the solvent was removed under reduced pressure
to yield 1.7 g (91%) of oil as a mixture of diastereomers of
compound 19 and a partly cyclized product: 1H-NMR (CDCl3,
δ) 0.9 (t, 3H, J ) 7.3 Hz), 1.4-1.6 (m, 1H), 1.6-1.9 (m, 2H),
2.35-2.5 (m, 1H), 2.9-3.0 (m, 2H), 3.1-3.3 (m, 1H), 3.7-3.9
(m, 2H), 3.8 (s, 3H), 4.8 (d, 1H, J ) 9.0 Hz), 5.4 (s, 1H), 6.7-
6.8 (m, 1H), 7.0-7.15 (m, 2H), 7.3-7.4 (m, 3H), 7.5-7.6 (m,
2H); 13C-NMR (CDCl3, δ) 9.7, 19.7, 23.7, 25.5, 41.6, 53.9, 55.2,
75.2, 79.8, 108.3, 113.2, 124.6, 126.5, 126.7, 127.7, 134.0, 136.8,
156.9, 167.3. The compound was used without further purifi-
cation.
1
°C; H-NMR (CD3OD, δ) 0.9 (t, 3H, J ) 7.1 Hz), 1.6-1.9 (m,
3H), 2.3-2.4 (m, 1H), 2.7-2.9 (m, 2H), 3.0-3.2 (m, 1H), 3.3-
3.5 (m, 3H), 4.2-4.3 (d, 1H, J ) 12.9 Hz), 4.7 (d, 1H, J ) 9.5
Hz), 5.5 (br s, 1H), 6.9 (d, 1H, J ) 8.5 Hz), 6.6-6.7 (m, 1H),
7.1 (s, 1H), 7.3-7.6 (m, 5H); 13C-NMR (CD3OD, δ) 9.8, 15.1,
20.4, 25.0, 49.5, 52.6, 61.9, 68.9, 69.6, 110.6, 114.4, 123.7, 124.9,
127.0, 128.0, 128.2, 133.3, 135.8, 154.7. Anal. (C21H25NO2‚HCl‚
1/2H2O) C, H, N.
N-n -P r op yl-3-th iop h en -2-yl-a ceta m id e. To a solution of
n-propylamine (5.9 g, 100 mmol) in dichloromethane (50 mL)
and 2 N NaOH (10 mL) was added dropwise 3-thienylacetyl
chloride 22 (2.8 g, 17.4 mmol) dissolved in dichloromethane
(10 mL). The reaction mixture was stirred for 2 h at room
temperature. The two layers were separated, and the aqueous
layer was extracted with dichloromethane (20 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure to yield 2.3
g (72%) of oil which solidified upon standing and was recrys-
tallized from ethyl acetate/hexane: 1H-NMR (CDCl3, δ) 0.8 (t,
3H, J ) 7.3 Hz), 1.4-1.5 (m, 2H), 3.16-3.22 (m, 2H), 3.6 (s,
2H), 5.6 (br s, 1H), 7.0-7.1 (m, 1H), 7.1-7.2 (m, 1H), 7.3-7.4
(m, 1H); 13C-NMR (CDCl3, δ) 9.7, 21.2, 36.6, 39.8, 122.2, 125.2,
127.0, 133.5, 169; IR (NaCl) 1641 cm-1 (CdO, amide). Anal.
(C9H13NOS) C, H, N.
N-n -P r op yl-(3-th iop h en -2-yl-eth yl)-a m in e (23). N-n-Pro-
pyl-3-thiophen-2-yl-acetamide (1.0 g, 5.5 mmol) was dissolved
in anhydrous THF (25 mL), and 2 M BH3‚Me2S (5.5 mL, 10.9
mmol) in anhydrous THF (20 mL) was slowly added at room
temperature. The mixture was stirred at room temperature
for 30 min and was subsequently refluxed for 1 h. The mixture
was allowed to cool to room temperature; successively MeOH
(3.5 mL), H2O (3.5 mL), and 4 N HCl (3.5 mL) were added,
and the mixture was stirred for another 30 min. The solvent
was evaporated, and the residue was dissolved in H2O and
washed with diethyl ether; the aqueous layer was made
alkaline with NaHCO3 and extracted with diethyl ether. The
combined organic layers were washed with brine, dried over
Na2SO4, and filtered, and the solvent was evaporated to yield
0.75 g (67%) of yellow oil: 1H-NMR (CDCl3, δ) 0.9 (t, 3H, J )
7.3 Hz), 1.5 (q, 2H, J ) 7.3 Hz), 1.5-1.6 (m, 2H), 2.5 (t, 2H,
J ) 7.2 Hz), 2.8 (s, 4H), 6.9-7.0 (m, 2H), 7.2-7.3 (m, 1H);
13C-NMR (CDCl3, δ) 10.2, 21.6, 29.2, 48.7, 50.2, 119.4, 124.0,
126.6, 138.8. Anal. Calcd for C9H15NS‚3/4H2O: C, 59.14; H,
9.10; N, 7.66. Found: C, 59.60; H, 8.68; N, 7.30. The amine
was converted to the HCl salt and recrystallized from diethyl
ether/2-propanol: mp 207-210 °C.
To a solution of the chloroacetamide (19) in 200 mL of
2-propanol was added a solution of 1.2 g of NaOH in 2.4 mL
of H2O dropwise at rt. After being stirred for 5 h at room
temperature, the mixture was neutralized with 1 N HCl. The
solvents were evaporated, and the resulting residue was
slurried in 200 mL of water and extracted with 4 × 25 mL of
dichloromethane. The organic layer was washed with water,
dried over Na2SO4, and then reduced to dryness. The residual
solid was purified by column chromatography on silica gel 60
using a mixture of EtOAc and hexane (1/4) as the eluent,
resulting in the separation of the two stereoisomers (20a and
20b). Recrystallization from isopropyl acetate gave the lactams
as white crystals. Fast-eluting compound (20a , axial): yield
1
590 mg (38%); mp 151.5-152 °C; H-NMR (CDCl3, δ) 1.0 (t,
3H, J ) 7.3 Hz), 1.5-1.9 (m, 3H), 2.3-2.5 (m, 1H), 2.8-3.0
(m, 2H), 3.4-3.5 (m, 1H), 3.6-3.8 (m, 2H), 3.8 (s, 3H), 4.6 (d,
1H, J ) 9.5 Hz), 5.6 (s, 1H), 6.8 (dd, 1H), 7.0 (d, 1H, J ) 8.3
Hz), 7.1 (br s, 1H), 7.3-7.4 (m, 3H), 7.6 (d, 2H, J ) 7.4 Hz);
13C-NMR (CDCl3, δ) 11.3, 21.3, 25.2, 26.7, 43.5, 55.2, 57.2, 71.3,
78.2, 109.5, 113.8, 126.0, 127.3, 127.9, 128.4, 129.1, 135.8,
137.2, 158.1, 167.5; IR (NaCl) 1651 cm-1 (CO); MS (M+) 351.
Slow-eluting compound 20b (equatorial): yield 840 mg
(55%); mp 112.5-113.5 °C; 1H-NMR (CDCl3, δ) 0.9 (t, 3H, J )
7.4 Hz), 1.4-1.6 (m, 1H), 1.6-1.9 (m, 2H), 2.4-2.5 (m, 1H),
2.9-3.0 (m, 2H), 3.1-3.3 (m, 1H), 3.8 (s, 3H), 3.8-4.0 (m, 2H),
4.80 (d, 1H, J ) 9.3 Hz), 5.4 (s, 1H), 6.9 (m, 1H), 7.0-7.2 (m,
2H), 7.5-7.6 (m, 3H), 7.7-7.8 (m, 2H); 13C-NMR (CDCl3, δ)
11, 21, 25, 27, 43, 55, 57, 77, 81, 110, 115, 126, 127.9, 128,
130, 135.5, 138, 158, 169; IR (NaCl) 1640 cm-1 (CO); MS (M+)
351. Anal. (C22H25NO3) C, H, N. The equatorial product is used
for the following step.
tr a n s-9-Meth oxy-2-p h en yl-4-N-n -p r op yl-2,3,4a ,5,6,10b-
h exa h yd r o-4H-n a p h th [1,2b][1,4]oxa zin e (21). To a solution
of amide 20a (350 mg, 1.0 mmol) in anhydrous THF (25 mL)
was added LiAlH4 (200 mg). The mixture was refluxed for 3
h, and then successively added were water (0.2 mL), 4 N NaOH
(0.2 mL), and water (0.6 mL). This mixture was refluxed for
another 15 min. The solid was filtered off, and the filtrate was
dried over Na2SO4 and concentrated to yield 316 mg (94%) of
N-n -P r op yl-(3-th iop h en -2-yl-eth yl)-th iop h en -2-yl-a ce-
ta m id e (24). To a solution of amine 23‚HCl (500 mg, 2.4
mmol) dissolved in dichloromethane (50 mL) and 10% NaOH
(10 mL) was added 2-thienylacetyl chloride (2 mL). The
mixture was stirred for 3 h at room temperature and poured
into water. The organic layer was separated, and the aqueous
layer was extracted with dichloromethane. The organic layers
were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The oil was purified over a SiO2
column with dichloromethane as the eluent. Evaporation of
the dichloromethane yielded 660 mg (93%) of oil: 1H-NMR
(CDCl3, δ) 0.9 (t, 3H, J ) 7.3 Hz), 1.4-1.7 (m, 2H), 2.8-2.9
(m, 2H), 3.1-3.2 (m, 1H), 3.3-3.4 (m, 1H), 3.5-3.7 (m, 4H),

3028 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Dijkstra et al.
6.8-7.0 (m, 4H), 7.2-7.3 (m, 2H); 13C-NMR (CDCl3, δ) 9.7
(C10), 9.9 (C10), 19.3 (C9 or C12), 20.8 (C9 or C12), 26.7 (C9
or C12), 28.1 (C9 or C12), 33.3 (C6), 33.4 (C6), 46.0 (C8 or C11),
46.2 (C8 or C11), 47.6 (C8 or C11), 49.1 (C8 or C11), 119.8,
120.3, 123.2, 124.1, 124.5, 124.8, 125.2, 126.5, 126.7, 135.2,
136.5, 137.8, 168.2 (C7). Anal. (C15H19NOS2) C, H, N.
3-(Tr im eth yla m m on iu m )-2-(tr im eth ylsilylm eth yl)th io-
p h en e Iod id e (28). To a stirred solution of 3-(dimethylami-
nomethyl)-2-(trimethylsilylmethyl)thiophene (27) (3 g, 0.013
mol) in acetonitrie (10 mL) was added iodomethane (1.3 mL,
0.021 mol). After being refluxed for 1 h, the mixture was cooled
to room temperature, and diethyl ether was added. The
mixture was filtered to yield 3.45 g (71%) of a yellow solid
compound: 1H-NMR (DMSO, δ) 0.0 (s, 9H), 2.5 (s, 2H), 3.0 (s,
9H), 4.4 (s, 2H), 7.1 (d, J ) 5.4 Hz, 1H), 7.3 (d, J ) 5.4 Hz,
1H); 13C-NMR (DMSO, δ) -1.4, 18.5, 51.7, 60.3, 122.3, 123.1,
130.8, 147.7 (ref 30).
N-n -P r op yl-(2-th iop h en -2-yl-eth yl)-th iop h en -3-yleth yl-
a m in e (3). N-n-Propyl-(3-thiophen-2-yl-ethyl)-thiophen-2-yl-
acetamide 24 (0.5 g, 1.70 mmol) was dissolved in anhydrous
THF (40 mL), and 2 M BH3‚Me2S (3 mL) in anhydrous THF
(10 mL) was slowly added at room temperature. The mixture
was stirred at room temperature for 30 min and subsequently
refluxed for 3 h. The mixture was allowed to cool to room
temperature; successively MeOH (3 mL), H2O (3 mL), and 12
N HCl (3 mL) were added, and the mixture was stirred for
another 30 min. The solvent was evaporated, and the residue
was dissolved in H2O and washed with diethyl ether; the
aqueous layer was made alkaline with the addition of NaHCO3
and extracted with diethyl ether. In both diethyl ether layers,
compound 3 was present, and therefore, all the organic layers
were combined. The combined organic layers were washed with
brine, dried over Na2SO4, and filtered, and the solvent was
evaporated to yield 0.33 g (69.3%) of a light yellow solid: mp
5- a n d 6-Meth ylca r boxyla te-4,5,6,7-tetr a h yd r oben zo-
[b]th iop h en e (29a ,b). To a stirred solution of 2-(trimethyl-
silylmethyl)-3-(trimethylammonium)thiophene iodide (28) (10
g, 0.03 mol) and methylacrylate (136 mL) in acetonitrile (270
mL) was added dropwise a solution of tetrabutylammonium-
fluoride trihydrate (17.1 g, 0.05 mol) in acetonitrile (540 mL)
in 2 h. After the addition was complete, the solution was
concentrated, and diethyl ether was added until no further
precipitate was formed. The mixture was filtered, and the
solvent was evaporated. Bulb-to-bulb distillation at 100 °C
(0.05 mmHg) yielded 4.2 g (81%) of oil: 1H-NMR (CDCl3, δ)
1.8-2.0 (m, 1H), 2.15-2.3 (m, 1H), 2.6-3.1 (m, 5H), 3.7 (s,
3H), 6.7 (d, 1H, J ) 5.1 Hz), 7.1 (d, 1H, J ) 5.1 Hz); 5-isomer
13C-NMR (CDCl3, δ) 23.9, 26.1, 27.8, 39.6, 51.6, 122.3, 127.2,
133.3, 134.3, 175.3; 6-isomer 13C-NMR (CDCl3, δ) 24.4, 25.6,
27.1, 40.3, 51.6, 122.3, 127.1, 133.3, 134.3, 175.3; the ratio of
6-isomer/5-isomer ) 2:1, which was determined by 13C-NMR;
IR (NaCl) 1739 cm-1 (CdO).
1
141.5-142.5 °C; H-NMR (CDCl3, δ) 0.9 (t, 3H, J ) 7.3 Hz),
1.5 (q, 2H, J ) 7.3 Hz), 2.5-2.6 (m, 2H), 2.8-2.9 (m, 6H), 3.0-
3.1 (m, 2H), 6.8 (m, 1H), 6.9-7.0 (m, 3H), 7.1-7.2 (m, 1H),
7.2-7.3 (m, 1H); 13C-NMR (CDCl3, δ) 10.5, 19.0, 26.4, 26.6,
53.5, 54.4, 54.5, 119.1, 121.8, 123.1, 123.7, 125.1, 126.9, 139.4,
141.7. Anal. (C15H21NS2‚ditoluoyl tartaric acid) C, H, N.
N-n -P r op yl-(3-th iop h en -2-yl-eth yl)-th iop h en -3-yl-a cet-
a m id e (25). N-n-Propyl-(3-thiophen-2-yl-ethyl)-amine 23 (1.0
g, 6.0 mmol) was dissolved in dichloromethane (50 mL), and
10% NaOH solution (10 mL) and 3-thienyl acetyl chloride (1.0
g, 6.2 mmol) in dichloromethane (20 mL) were added. The
reaction mixture was stirred for 2 h at room temperature. The
two layers were separated, and the organic layer was washed
with 3 N HCl solution and water and dried over Na2SO4, and
the solvent was evaporated to yield 1.2 g (85.7%) of yellow oil:
1H-NMR (CDCl3, δ) 0.9 (dt, 3H, J ) 7.3 Hz), 1.4-1.7 (m, 2H),
2.7-2.9 (m, 2H), 3.0-3.2 (m, 1H), 3.3-3.4 (m, 1H), 3.5-3.7
(m, 4H), 6.8-7.0 (m, 4H), 7.2-7.3 (m, 2H); 13C-NMR (CDCl3,
δ) 9.7 (C10), 9.9 (C10), 19.3 (C9 or C12), 20.7 (C9 or C12), 26.7
(C9 or C12), 28.0 (C9 or C12), 34.3 (C6), 45.6 (C8 or C11), 46.0
(C8 or C11), 47.6 (C8 or C11), 48.9 (C8 or C11), 119.7, 120.2,
120.4, 120.5, 124.0, 124.3, 124.7, 126.5, 126.8, 127.2, 133.5 (C4
or C13), 133.6 (C4 or C13), 136.8 (C4 or C13), 137.8 (C4 or
C13), 169.1 (C7); IR (NaCl) 1642 cm-1 (CdO, amide). Anal.
(C15H19NOS2‚1/2H2O) C, H, N.
N-n -P r op yl-(3-th iop h en -2-yl-eth yl)-th iop h en -3-yleth yl-
a m in e (4). This compound was synthesized in 67% yield
according to the method used for compound 3: mp 117-119
°C; 1H-NMR (CDCl3, δ) 0.9 (t, 3H, J ) 7.3 Hz), 1.5-1.8 (m,
2H), 2.8-3.0 (m, 4H), 3.0-3.2 (m, 4H), 6.9-7.1 (m, 4H), 7.2-
7.3 (m, 2H); 13C-NMR (CDCl3, δ) 10.1, 14.8, 23.0, 53.0, 58.5,
119.9, 124.6, 126.5, 136.7. Anal. (C15H21NS2‚HCl‚1/4H2O) C, H,
N.
3-(Dim et h yla m in om et h yl)-2-(t r im et h ylsilylm et h yl)-
th iop h en e (27). To a cooled solution of 2-bromo-3-(dimeth-
ylaminomethyl)thiophene (26) (47 g, 0.21 mol) and bis-
(triphenylphosphine)nickel(II) chloride (1.4 g, 2.6 mol %) in
anhydrous diethyl ether (500 mL) was added dropwise a
solution of trimethylsilylmethylmagnesium chloride (prepared
from magnesium (8.9 g, 0.37 mol), a crystal iodine, and
chloromethyltrimethylsilane (40.9 g, 0.34 mol)) in anhydrous
diethyl ether (20 mL). After being refluxed for 20 h, the
mixture was cooled, andwater (160 mL) and aqueous saturated
NH4Cl solution (160 mL) were slowly added. The two layers
were separated, and the aqueous layer was extracted with
diethyl ether. The combined diethyl ether layers were washed
with brine, dried over Na2SO4, and filtered, and the solvent
was evaporated to yield 37 g (76%) of an oil: 1H-NMR (CDCl3,
δ) 0.02 (s, 9H), 2.16 (s, 6H), 2.2 (s, 2H), 3.2 (s, 2H), 6.9 (s, 2H);
13C-NMR (CDCl3, δ) -1.7, 18.1, 45.0, 56.5, 119.3, 129.1, 132,
138 (ref 30).
4,5,6,7-Tetr a h yd r oben zo[b]th iop h en e-5- a n d -6-Ca r -
boxylic Acid (30a ,b). A solution of 4,5,6,7-tetrahydrobenzo-
[b]thiophene-5- and -6-carboxylate (29a ,b) (4.29 g, 22 mmol)
in an aqueous 16% NaOH solution (35 mL) was refluxed for
45 min. After the mixture had been cooled to rt, an aqueous 2
N HCl solution was added until the pH was 1. A white solid
was formed which dissolved in dichloromethane. The aqueous
layer was saturated with NaCl and extracted with dichlo-
romethane. The combined organic layers were dried over Na2-
SO4 and filtered, and the solvent was evaporated to yield 3.87
g (97%) of a pale yellow solid: mp 82.5-84.5 °C; 1H-NMR
(CDCl3, δ) 1.8-2.1 (m, 1H), 2.2-2.3 (m, 1H), 2.7-3.1 (m, 5H),
6.8 (d, 1H, J ) 5.1 Hz), 7.1 (d, 1H, J ) 5.1 Hz); 5-isomer 13C-
NMR (CDCl3, δ) 23.7, 25.8, 27.5, 39.5, 122.3, 127.2, 133.0,
134.3, 181.5; 6-isomer 13C-NMR (CDCl3, δ) 24.3, 25.3, 26.8,
40.1, 122.3, 127.1, 133.0, 134.3, 181.2. A 2:1 ratio of the
6-isomer:5-isomer was determined by 13C-NMR.
5- a n d 6-Am m on iu m -4,5,6,7-tetr a h yd r oben zo[b]th io-
p h en e Hyd r och lor id e (31a ,b). To a solution of a mixture of
30a and 30b (4.26 g, 23 mmol) and triethylamine (3.62 g, 24
mmol) in dioxane (120 mL) was added diphenylphosphoryl
azide (5.3 mL, 24 mmol) at 5 °C. The reaction mixture was
stirred overnight at room temperature. Diethyl ether (300 mL)
and water (300 mL) were added to the reaction mixture. After
separation of the two layers, the organic layer was washed
with a 1% NaOH solution, dried over Na2SO4, and concen-
trated under reduced pressure, yielding a red residue which
was used without purification for the next step. To the residue
were added aqueous 1 N HCl (110 mL) and dioxane (110 mL),
and the mixture was heated for 2 h at 120 °C. The mixture
was allowed to cool to room temperature, and it was basified
(pH 10) with 4 N NaOH, extracted with diethyl ether, and
dried over Na2SO4. Filtration and evaporation of the organic
solvents gave a brown oil which dissolved in diethyl ether. Slow
addition of an ethereal HCl solution gave a light brown solid.
The yield of the obtained mixture of regioisomers (31a ,b) was
2.6 g (58%): mp 192.8-194.1 °C; 1H-NMR (CDCl3, δ) 1.5-1.7
(m, 1H), 1.9-2.0 (m, 1H), 2.4-3.0 (m, 4H), 3.1-3.3 (m, 1H),
6.7 (d, 1H, J ) 5.1 Hz), 7.0 (d, 1H, J ) 5.1 Hz); 5-isomer 13C-
NMR (CDCl3, δ) 21.9, 31.8, 34.0, 45.9, 121.0, 126.0, 132.1,
132.4; 6-isomer 13C-NMR (CDCl3, δ) 22.4, 31.1, 33.3, 46.4,
120.9, 125.7, 132.1, 132.9; IR (KBr) 3300 and 1618 cm-1 (NH2).
A 2:1 ratio of the 6-isomer:5-isomer was determined by 13C-
NMR.

Requirements for Ligands at the Dopamine Receptor
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3029
5- a n d 6-(N-(Di-n -p r op yl))a m in o-4,5,6,7-tetr a h yd r oben -
zo[b]th iop h en e (10 a n d 11). To a stirred solution of 5- and
6-ammonium-4,5,6,7-tetrahydrobenzo[b]thiophene chloride
(31a ,b) (2.5 g, 0.013 mol) and K2CO3 (7.05 g, 0.05 mol) in DMF
(370 mL) was added 1-iodopropane (9 mL, 0.092 mmol). After
being stirred for 24 h at 50 °C, the solution was poured into
water and extracted 5 times with diethyl ether. The combined
diethyl ether layers were washed 6 times with brine, dried
over Na2SO4, filtered, and evaporated to yield 3 g (84%). It is
possible to separate both isomers by column chromatography
with the eluent EtOAc/hexane (1:9). After evaporation of the
solvent, the isomers were dissolved in anhydrous diethyl ether,
and 1 N HCl in diethyl ether was added to yield 1.3 g (36%) of
the 6-isomer and 650 mg (18%) of the 5-isomer. 6-Isomer: mp
Hz), 7.1 (d, 1H, J ) 5.1 Hz); 5-isomer mp 118.5-120.5 °C; 13C-
NMR (CDCl3, δ) 11.7, 20.2, 24.3, 28.3, 30.5, 32.9, 56.7, 60.2,
121.7, 127.5, 135.2, 135.3. Anal. (C15H25NS‚1/4H2O) C, H, N.
6-Isomer: mp 79-81 °C; 13C-NMR (CDCl3, δ) 11.7, 20.2, 24.8,
27.6, 29.8, 33.8, 56.7, 60.2, 121.6, 127.2, 135.2, 135.3. Anal.
(C15H25NS‚C4H4O4) C, H, N.
6,7-Dih yd r o-5H-ben zo[b]th iop h en -4-on e Oxim e (35).
6,7-Dihydro-5H-benzo[b]thiophene-4-one (34) (10.0 g, 66.0
mmol) was dissolved in ethanol (120 mL) and water (12 mL).
To this solution were added sodium acetate (11 g, 134 mmol)
and hydroxylammoniumchloride (8.67 g, 125 mmol). This
mixture was refluxed for 3 h, and then cooled to room
temperature. Cold water was added, and the precipitate
obtained was filtered, washed with water, and dried to yield
13.06 g (118%) that was not pure. Recrystallization of the
white precipitate from ethanol gave white crystals: mp 125-
127 °C; IR (KBr) 3289 cm-1 (CdN); 1H-NMR (CDCl3, δ) 2.0 (t,
2H, J ) 6.3 Hz), 2.8-2.9 (m, 4H), 7.1 (d, 1H, J ) 5.3 Hz), 7.3
(d, 1H, J ) 5.4 Hz); 13C-NMR (CDCl3, δ) 22.2, 22.6, 24.8, 122.9,
123.1, 131, 143.7, 153.1. Anal. (C8H9NOS) C, H, N.
1
134-135 °C; H-NMR (CDCl3, δ) 1.0 (t, 6H, J ) 7.3 Hz), 1.8
(q, 4H, J ) 7.6 Hz), 2.0-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.7-3.0
(m, 2H), 3.0-3.4 (m, 6H), 3.7-3.9 (m, 1H), 6.8 (d, 1H, J ) 5.1
Hz), 7.2 (d, 1H, J ) 5.1 Hz); 13C-NMR (CDCl3, δ) 9.6, 18.0,
18.2, 23.5, 23.6, 24.7, 52.2, 52.7, 60.5, 123.4, 126.3. Anal.
(C14H23NS‚HCl) C, H, N. 5-Isomer: mp 134-136 °C; 1H-NMR
(CDCl3, δ) 1.0 (t, 6H, J ) 7.2 Hz), 1.8 (q, 6H, J ) 7.3 Hz),
2.0-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.8-3.0 (m, 2H), 3.0-3.3
(m, 6H), 3.7-3.9 (m, 1H), 6.8 (d, 1H, J ) 5.1 Hz), 7.2 (d, 1H,
J ) 5.1 Hz); 13C-NMR (CDCl3, δ) 9.6, 18.0, 18.3, 23.1, 24.1,
6,7-Dih yd r o-5H-ben zo[b]th iop h en -4-on e O-Tosyloxim e
(36). A solution of oxime 35 (4.0 g, 23.9 mmol) in 25 mL of
pyridine was cooled to about 10 °C in an ice bath. p-Toluene
sulfonyl chloride (10.3 g, 53.9 mmol) was added slowly in small
portions. This mixture was stirred for 2 h at about 10 °C, and
then for 2 h at room temperature. The mixture was then
poured into ice water. The precipitate obtained was filtered,
washed with water, and dried. The yield was 7.84 g (100%)
that was not pure. Recrystallization of the white precipitate
from ethyl acetate gave white crystals: mp 130-132 °C; IR
25.4, 52.2, 52.7, 60.2, 123.4, 126.7, 131, 133.5. Anal. (C14H23
-
NS‚HCl‚1/4H2O) C, H, N.
5- a n d 6-(N-(Di-n -p r op yl))m eth ylen ea m in o-4,5,6,7-tet-
r a h yd r oben zo[b]th iop h en e (12, 13). To a cooled and stirred
solution of 4,5,6,7-tetrahydrobenzo[b]thiophene-5- and -6-car-
boxylic acid (30a ,b) (2.7 g, 0.015 mol) in anhydrous dichloro-
methane (40 mL) was added dropwise under nitrogen oxalyl
chloride (5.9 mL, 8.9 g, 0.068 mol). The mixture was stirred
overnight at room temperature and evaporated to yield 2.9 g
(96%) of an oil of compound 33a ,b: 1H-NMR (CDCl3, δ) 1.9-
2.2 (m, 1H), 2.3-2.5 (m, 1H), 2.7-3.3 (m, 5H), 6.8 (d, 1H, J )
5.0 Hz), 7.1 (d, 1H, J ) 5.0 Hz); 5-isomer 13C-NMR (CDCl3, δ)
23.5, 26.3, 28.0, 51.6, 123.0, 127.0, 132.0, 134.3, 176.1; 6-isomer
13C-NMR (CDCl3, δ) 24.0, 25.8, 27.4, 52.0, 123.0, 127.0, 131.8,
134.1, 176.1. A 2:1 ratio of the 6-isomer:5-isomer was deter-
mined by 13C-NMR. The reaction product was used for the next
step without further purification and analysis.
To a stirred solution of 4,5,6,7-tetrahydrobenzo[b]thiophene-
5- and -6-carbanoyl chloride (32a ,b) (1.8 g, 8.8 mmol) in
dichloromethane (100 mL) was added dropwise a mixture of
di-n-propylamine (1.8 mL, 1.3 g, 0.013 mmol) and triethyl-
amine (1.3 mL, 0.95 g, 0.010 mmol) in dichloromethane. After
being stirred for 3 h at room temperature, the mixture was
evaporated, and the residue was dissolved in diethyl ether.
The diethyl ether layer was extracted 4 times with 4 N HCl,
dried over Na2SO4, and evaporated. Purification with column
chromatography (SiO2) with the eluent EtOAc:hexane (1:9)
yielded 1.66 g (71%) of an oil of compound 33a ,b: 1H-NMR
(CDCl3, δ) 0.9 (t, 6H, J ) 7.4 Hz), 1.5-1.6 (m, 4H), 1.9-2.0
(m, 2H), 2.7-3.0 (m, 5H), 3.2-3.3 (m, 4H), 6.7 (d, 1H, J ) 5.1
Hz), 7.0 (d, 1H, J ) 5.1 Hz); 5-isomer 13C-NMR (CDCl3, δ) 10.9,
11.1, 20.7, 22.6, 24.4, 27.2, 28.8, 37.1, 47.4, 49.3, 122.1, 127.3,
134.1, 134.2, 174.6; 6-isomer 13C-NMR (CDCl3, δ) 10.9, 11.1,
20.7, 22.6, 24.9, 26.7, 28.1, 37.7, 47.4, 49.3, 122.0, 127.1, 134.1,
134.2, 174.6. A 2:1 ratio of the 6-isomer:5-isomer was deter-
mined by 13C-NMR. The reaction product was used for the next
step without further purification and analysis.
1
(KBr) 1596 cm-1 (CdN); H-NMR (CDCl3, δ) 1.9 (t, 2H, J )
6.2 Hz), 2.4 (s, 3H), 2.8-2.9 (m, 4H), 7.0 (d, 1H, J ) 5.2 Hz),
7.2 (d, 1H, J ) 5.3 Hz), 7.4 (d, 2H, J ) 8.3 Hz), 7.9 (d, 2H,
J ) 8.8 Hz); 13C-NMR (CDCl3, δ) 21.8, 22.3, 23.8, 24.6, 123.2,
123.4, 128.8, 128.9, 129.5, 133, 145, 148, 159. Anal. (C15H15
-
NO3S2‚1/2H2O) C, H, N.
5-Am in o-6,7-d ih yd r o-5H-ben zo[b]th iop h en e-4-on e (37).
A solution of potassium tert-butoxide (5.7 g, 50.8 mmol),
ethanol (43 mL), and toluene (107 mL) was cooled to 0-5 °C.
To this solution was added 4-tosyloxime-4,5,6,7-tetrahy-
drothianaphthene (36) (10.0 g, 31.6 mmol). This mixture was
stirred for 2 h at 0-5 °C, and then stirred for 2 h at room
temperature. The precipitate (potassium tosylate) obtained
was filtered and washed with diethyl ether. To the filtrate was
added 5 mL of 37% HCl. After the mixture had been stirred
for some time, a precipitate arose of the ketamine‚HCl 37. The
precipitate was filtered and washed with diethyl ether, and
the yield was 4.5 g (71%) before recrystallization; after
recrystallization of the precipitate from ethanol/diethyl ether,
yellow crystals were obtained: mp 197-199 °C; IR (KBr) 3430
1
(NH), 1600, 1500 (NH), 1676 cm-1 (CdO); H-NMR (CD3OD,
δ) 2.3-2.5 (m, 1H), 2.6-2.7 (m, 1H), 3.3-3.4 (m, 2H), 4.3-4.4
(dd, 1H, J ) 13.7 Hz), 7.4 (s, 2H); 13C-NMR (CD3OD, δ) 24.6,
30.2, 55.7, 124.9, 126.4, 135, 158, 188.
2-Ch lor o-N-(4-oxo-4,5,6,7-tetr ah ydr oben zo[b]th ioph en e-
5-yl)-a ceta m id e (38). To a solution of amino ketone 37 (5.3
g, 21.1 mmol) in dichloromethane (290 mL) was added a
solution of NaOH (7.1 g, 0.18 mol) in water (61 mL). To this
stirred mixture was added chloroacetyl chloride (5.9 g, 4.2 mL,
51.9 mmol), and the mixture was stirred for another 3 h. After
the reaction was complete, the organic layer was separated.
To the water layer were added water (145 mL) and 4 N HCl
until the water layer was neutral. The water layer was
extracted with dichloromethane (3 × 25 mL). The combined
organic layers were washed with brine, dried over Na2SO4, and
evaporated. Recrystallization from ethyl acetate/hexane yielded
6.0 g (95%) of brown crystals: mp 130-132 °C; IR (KBr) 3334
(NH), 1681 (CdO), 1639 cm-1 (CdO, amide); 1H-NMR (CDCl3,
δ) 1.9-2.1 (m, 1H), 2.8-2.9 (m, 1H), 3.15-3.25 (m, 1H), 4.1
(s, 2H), 4.5-4.65 (m, 1H), 7.1 (d, 1H, J ) 5.3 Hz), 7.3 (d, 1H,
J ) 5.4 Hz), 7.6 (m, 1H); 13C-NMR (CD3OD, δ) 24.6, 31.3, 42.6,
55.9, 124.5, 124.7, 135.6, 155.7, 166.4, 189. Anal. (C10H10NO2-
SCl) C, H, N.
A solution of 4,5,6,7-tetrahydrobenzo[b]thiophene-5- and-
6-carboxylic amide (33a ,b) (5 g, 19 mmol) in anhydrous THF
(340 mL) was cooled to 0-5 °C, and LiAlH4 (3.6 g, 95 mmol)
was added. The mixture was refluxed for 3 h; it was then
cooled to room temperature, and 3.6 mL of water, 3.6 mL of 4
N NaOH solution, and 10.8 mL of water were added. The
mixture was filtered; the precipitate was washed with diethyl
ether, and the filtrate was dried over Na2SO4. Evaporation of
the solvent yielded 4.5 g (92%) of crude oil. Purification and
separation over a SiO2 column with the eluent CH2Cl2/MeOH
(20:1) yielded 3.7 g of 6-isomer and 1 g of 5-isomer: 1H-NMR
(CDCl3, δ) 0.9 (t, 6H, J ) 7.3 Hz), 1.4-1.5 (m, 6H), 1.9-2.1
(m, 2H), 2.3-2.5 (m, 6H), 2.7-3.0 (m, 3H), 6.8 (d, 1H, J ) 5.1

3030 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Dijkstra et al.
tr a n s-2-Ch lor o-N-(4-h yd r oxy-4,5,6,7-tetr a h yd r oben zo-
[b]th iop h en e-5-yl)-a ceta m id e (39). A solution of chloroac-
etamide (38) (4.0 g, 16.4 mmol) in methanol (90 mL) under
nitrogen was cooled to 5-8 °C in an ice bath. While the
mixture was being stirred, a solution of NaBH4 (1.5 g, 39.6
mmol) was added in portions. The solution was stirred for
another hour at 5-8 °C. To the mixture was added 1 N HCl
to remove excess of NaBH4, and then the solvent was evapo-
rated. Recrystallization of the crude product from ethyl acetate/
hexane yielded 3.55 g (88%) of brown crystals: mp 148-150
1H, 5.2 Hz); 13C-NMR (CDCl3, δ) 10.9, 17.6, 23.4, 24.1, 52.6,
55.4, 65.0, 65.6, 76.7, 125.3, 125.5, 135, 147. Anal. (C13H19
-
NOS‚HCl) C, H, N.
Dist a n ce Ca lcu la t in g. Conformational analyses were
performed in MacroModel version 6.5 on a Silicon Graphics
O2 workstation.33 All ligands were considered in their pro-
tonated, positively charged forms (MM3* force field34), and
were minimized using the Truncated Newton Conjugate
Gradient (TNCG) minimizer in a simulated distance-depend-
ent GB/SA water continuum.35 After the minimization, the
distances were calculated.
1
°C; IR (KBr) ∼3200 (OH), 1646 cm-1 (CdO, amide); H-NMR
(CDCl3, δ) 1.85-2.05 (m, 1.5H), 2.15-2.3 (m, 1.5H), 2.8-3.0
(m, 2H), 4.1 (s, 2H), 4.2 (m, 1H), 4.6 (d, 1H, J ) 7.17 Hz), 6.7
(br s, 1H), 7.1 (d, 1H, J ) 5.0 Hz), 7.2 (d, 1H, J ) 5.1 Hz);
13C-NMR 23.3, 27.6, 42.9, 54.1, 69.8, 124.1, 127.4, 127.5, 128,
169. Anal. (C10H12NO2SCl) C, H, N.
P h a r m a cology. Cell Lin es Exp r essin g Dop a m in e (DA)
Recep tor Isofor m s. A cell line expressing the human DA D2L
was purchased from Dr. O. Civelli (Oregon Health Sciences
University). The D2L receptor cDNA was subcloned into the
expression vector, pRc/CMV. The plasmids were transfected
by electroporation into CHO K1 cells. A single stable trans-
fectant, resistant to the antibiotic G418, was isolated and
selected for use in the binding studies. The human DA D3
receptor cDNA cloned in the pcDNAIneo plasmid was obtained
from Dr. K. O’Malley and stably transfected into CHO K1 cells
by a modified calcium phosphate precipitation technique.36
Transfectants were selected in G418, isolated, and screened
for the expression of human D3 receptors by radioligand
binding as previously described.37
tr a n s-4,5a ,6,9a -Tetr a h yd r o-5H-9-oxa -6-a za -cyclop en ta -
[a ]n a p h th a len e-7-on e (40). To a solution of 4-hydroxyamide
(39) (5.2 g, 21.16 mmol) in 2-propanol (275 mL) was added
dropwise 50% NaOH solution (3.6 mL) at room temperature.
The solution was stirred for 15 h. After the reaction was
complete, the solvent was evaporated until almost dry. The
suspension was diluted with water (180 mL), neutralized with
10% HCl, and extracted with dichloromethane. The combined
organic layers were washed with brine, dried over Na2SO4, and
evaporated. Recrystallization of the crude product from ethyl
acetate/hexane yielded 2.0 g (45%) of brown crystals: mp 242-
244 °C; IR (KBr) 3313 (NH), 1638 cm-1 (CdO); 1H-NMR
(CDCl3, δ) 1.9-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.9-3.0 (m, 2H),
3.6-3.7 (m, 1H), 4.4 (d, 2H, J ) 2.7 Hz), 4.47-4.53 (m, 1H),
7.0 (d, 1H, J ) 5.2 Hz), 7.2 (d, 1H, J ) 5.2 Hz), 7.9 (br s, 1H);
13C-NMR 23.5, 27.6, 53.8, 68.3, 76.1, 124.2, 124.5, 133.9, 136.3,
170.2. Anal. (C10H11NO2S) C, H, N.
Cell Cu ltu r e a n d P r ep a r a tion of Cell Mem br a n es.
CHO K1 cells expressing either human DA D2L or D3 receptors
were grown in 162 cm2 culture flasks in F12 medium (Gibco
Laboratories, Grand Island, NY) supplemented with 10% fetal
bovine serum (FBS, Hyclone, Logan, UT) in an atmosphere of
5% CO2/95% air at 37 °C. Cells were grown until confluent,
after which growth medium was removed and replaced with
0.02% EDTA in a phosphate-buffered saline solution (Sigma
Chemical Co., St. Louis, MO), and the cells were scraped from
the flasks. The cells were centrifuged at about 1000g for 10
min at 4 °C; they were then resuspended in TEM buffer (25
mM Tris-HCl, pH 7.4 at 37 °C, 1 mM EDTA, and 6 mM CaCl2)
for D2L and D3 and homogenized with a Brinkman Polytron
homogenizer at setting 5 for 10 s. The membranes were
pelleted by centrifugation at 20000g at 4 °C for 20 min, and
then the pellets were resuspended in the appropriate buffer
at 1 mL/flask and stored at -70 °C until they were used in
the receptor binding assay.
tr a n s-2,3,4a,5,6,9b-Hexah ydr o-4H-th ian aph th [4,5e][1,4]-
oxa zin e (14). A solution of trans-2,3,4a,5,6,9b-hexahydro-4H-
thianaphth[4,5e][1,4]oxazine-3-one (40) (1.3 g, 6.2 mmol) in
anhydrous THF (195 mL) was cooled to about 5 °C. To this
solution was added LiAlH4 (845 mg, 22.3 mmol). This mixture
was refluxed for 2 h, and then cooled to room temperature.
Water (0.9 mL), 4 N NaOH solution (0.9 mL), and water (2.7
mL) were successively added to remove excess LiAlH4. The
mixture was filtered and washed with diethyl ether, and the
filtrate was dried over Na2SO4. Evaporation under reduced
pressure of the solvent yielded an oil.The oil was dissolved in
anhydrous diethyl ether which was saturated with gaseous
HCl. Recrystallization from 2-propanol anhydrous diethyl
ether yielded 245 mg (17%) of white crystals: mp 264-266
°C; IR (KBr) 3213 cm-1 (NH); 1H-NMR (CDCl3, δ) 1.2-1.3 (m,
1H), 2.1-2.3 (m, 1H), 2.4-2.6 (m, 1H), 2.9-3.1 (m, 2H), 3.2-
3.3 (m, 1H), 3.3-3.5 (m, 2H), 3.7-3.8 (m, 1H), 3.9-4.0 (m, 1H),
4.8-4.9 (m, 1H), 7.0 (d, 1H, J ) 5.4 Hz), 7.3 (d, 1H, J ) 5.4
Hz); 13C-NMR (CDCl3, δ) 23.9, 26.1, 45.2, 58.0, 64.8, 76.3,
125.1, 125.5, 134.5, 136.5. Anal. (C10H13NOS‚HCl‚1/4H2O) C,
H, N.
Recep tor Bin d in g Assa ys: D2L a n d D3 DA Recep tor s.
A cell membrane preparation (400 µL) was incubated in
triplicate with 50 µL of [3H]N-0437 (2 nM for D2L) or [3H]-
spiperone (0.5 nM for D3), 50 µL of buffer, or competing drugs
where appropriate to give a final volume of 0.5 mL. After 60
min of incubation at 25 °C, the incubations were terminated
by the rapid filtration through Whatmann GF/B glass fiber
filters (soaked for 1 h in 0.5% polyethylenimine) on a Brandel
MB-48R cell harvester and by 3 washes with 1 mL of ice-cold
buffer. Individual filter disks containing the bound ligand were
placed in counting vials with 4 mL of scintillation fluid (Ready
Gel, Beckman Instrument Inc., Fullerton, CA), and then
counted in a Beckman LS-6800 liquid scintillation counter at
an efficiency of 45%. Nonspecific binding was defined in the
presence of 1 µM haloperidol.
Da ta Ca lcu la tion . Saturation and competition binding
data were analyzed using the iterative nonlinear least-squares
curve-fitting Ligand program. In competition experiments,
apparent Ki values were calculated from IC50 values by the
method of Cheng and Prusoff.38 Experimental compounds were
made up as stock solutions in dimethyl sulfoxide (DMSO). The
final concentration of 0.1% DMSO used in the incubation
mixture had no effect on the specific binding. Each observation
was carried out in triplicate. To allow for these calculations,
Kd values were measured for the interaction of various ligands
with the receptor. The interactions measured were for the
following: [3H]spiperone binding, human D3, 0.15 ( 0.02 nM
(n ) 3); and [3H]N-0437 binding, human D2L, 2.24 ( 0.05 nM
(n ) 3).
t r a n s-N -n -P r op yl-2,3,4a ,5,6,9b -h e xa h yd r o-4H -t h ia -
n a p h th [4,5e][1,4]oxa zin e (15). To a solution of trans-2,3,-
4a,5,6,9b-hexahydro-4H-thianaphth[4,5e][1,4]oxazine (14) (100
mg, 0.43 mmol) in DMF (12 mL) under nitrogen were added
anhydrous K2CO3 (230 mg, 1.7 mmol) and 1-iodopropane (490
mg, 290 µL, 2.9 mmol). This mixture was stirred at 55 °C for
2.5 h. From TLC (with 10:1 CH2Cl2/MeOH as the eluent), it
was clear that the reaction was not finished, so additional
1-iodopropane was added, and the mixture was allowed to
stand over the weekend at room temperature. The mixture
was poured into water (20 mL) and extracted with diethyl
ether (5 × 20 mL). The combined extracts were washed with
brine (6 × 20 mL), dried over Na2SO4, and evaporated. The
resulting oil was dissolved in anhydrous diethyl ether, and
diethyl ether saturated with gaseous HCl was added to prepare
the HCl salt in a yield of 94.35 mg (80%): mp 238-240 °C;
1H-NMR (CDCl3, δ) 1.1 (t, 3H, J ) 7.3 Hz), 1.7-2.1 (m, 3H),
2.6-2.8 (m, 1H), 3.0-3.2 (m, 3H), 3.3-3.7 (m, 4H), 4.1-4.2
(m, 2H), 4.8 (d, 1H, J ) 9.1 Hz), 7.0 (d, 1H, J ) 5.1 Hz), 7.2 (d,

Requirements for Ligands at the Dopamine Receptor
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