trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: Synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist

Article abstract of DOI:10.1021/jm0604979

We report the synthesis of trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H- chromeno[3,4-c]isoquinoline hydrochloride 6 and the resolution of its enantiomers. This new compound is an oxygen bioisostere of the potent dopamine D₁-selective full agonist dihydrexidine. The initial synthetic approach involved, as a key step, a Suzuki coupling between a chromene triflate and a boronate ester, followed by isoquinoline formation and reduction of the resulting isoquinoline. Subsequently, a more efficient route was developed that involved conjugate addition of an aryl Grignard reagent to a 2-nitrochromene. The title compound possessed high affinity (K_i = 20-30 nM) for porcine D₁-like receptors in native striatal tissue and full intrinsic activity at cloned human dopamine D1 receptors but had much lower affinity at dopamine D₂-like receptors (K_i = 3000 nM). The binding and functional properties of this compound illustrate again the utility of constructing dopamine D₁ agonist ligands around the β-phenyldopamine pharmacophore template.

Full text of DOI:10.1021/jm0604979

6848
J. Med. Chem. 2006, 49, 6848-6857
trans-2,3-Dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: Synthesis,
Resolution, and Preliminary Pharmacological Characterization of a New Dopamine D1
Receptor Full Agonist
Juan Pablo Cueva, Gianfabio Giorgioni,† Russell A. Grubbs, Benjamin R. Chemel, Val J. Watts, and David E. Nichols*
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue UniVersity,
West Lafayette, Indiana 47907
ReceiVed April 27, 2006
We report the synthesis of trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline
hydrochloride 6 and the resolution of its enantiomers. This new compound is an oxygen bioisostere of the
potent dopamine D1-selective full agonist dihydrexidine. The initial synthetic approach involved, as a key
step, a Suzuki coupling between a chromene triflate and a boronate ester, followed by isoquinoline formation
and reduction of the resulting isoquinoline. Subsequently, a more efficient route was developed that involved
conjugate addition of an aryl Grignard reagent to a 2-nitrochromene. The title compound possessed high
affinity (Ki ) 20-30 nM) for porcine D1-like receptors in native striatal tissue and full intrinsic activity at
cloned human dopamine D1 receptors but had much lower affinity at dopamine D2-like receptors (Ki )
3000 nM). The binding and functional properties of this compound illustrate again the utility of constructing
dopamine D1 agonist ligands around the â-phenyldopamine pharmacophore template.
Introduction
schizophrenia.8 Indeed, the NIMH-sponsored MATRICS pro-
gram identified D1 receptors as the target of choice by
schizophrenia researchers for treating cognitive deficits in
schizophrenia. A recently completed proof-of-principle clinical
trial of dihydrexidine in schizophrenia has demonstrated a
significant increase in cortical blood flow, with a decrease in
reaction time and improvement in working memory (George et
al., unpublished results). The role of dopamine in mediating
key aspects of behavioral reinforcement, conditioning, and
learning has also been well documented.9 For example, D1
agonists have been shown to increase the latency of cocaine
self-administration in rats.10
Dopamine mediates and modulates neurotransmission in
neural pathways critical to important aspects of behavior and
cognition. Its physiological and pharmacological effects are
mediated by G-protein-coupled receptors that are the products
of at least five distinct genes.1 These dopamine-specific receptor
proteins have been categorized into two main families. The D1-
like receptors,2 D1 and D5, typically activate adenylate cyclase
through coupling with GRs/GRolf subunits, leading to increases
in cAMP. D2-like receptors, by contrast, are coupled to GRi/
GRo subunits and either inhibit adenylate cyclase or couple to
other effector systems.3
Extensive research into Parkinson’s disease has shown that
dopaminergic projections from the substantia nigra to the
striatum are vital to the initiation and control of motor
movement. Degeneration of this nigrostriatal pathway leads to
the classical symptoms of the disease: tremors, rigidity, and
slowness of movement.4 As such, the treatment of Parkinson’s
disease has been aimed at enhancing dopaminergic signaling
in the central nervous system (CNS), mainly through the use
of L-DOPA (a biosynthetic precursor of dopamine) and to a
lesser extent the use of bioavailable D2-like dopamine agonists
such as pergolide, pramipexole, and ropinirole.5
It is also becoming clear that dopamine D1 receptors are
involved in a variety of crucial cognitive functions, as well as
substance abuse disorders. For example, in the prefrontal cortex,
working memory processes appear to depend critically on a
proper level of D1 signaling.6 In the hippocampus, it has been
shown that D1 receptor activation strengthens the late phase of
long-term potentiation of synaptic transmission,7 believed to be
a key mechanism of memory consolidation.
The accumulating evidence for the critical importance of
dopamine D1 receptors in CNS function makes it imperative
that more tools be created to facilitate understanding of the role
of D1 receptors in the brain. Thus, for many years we have been
pursuing the development of receptor subtype-specific ligands
with the goal of understanding the physiological role that these
receptors play in behavior and cognition. The successful strategy
we have relied upon is based on the design of conformationally
rigid analogues of dopamine that presumably mimic the
geometry of dopamine when it binds to its receptors.
Early during this inquiry we discovered that attaching an aryl
group to the â position of the dopamine moiety conferred D1
selectivity and high intrinsic activity.11 Thus, several rigid
ligands containing this basic “â-phenyldopamine” pharmacoph-
ore have been developed that demonstrated both selectivity and
full agonist activity at the D1 receptor subtype. The first of these
compounds, dihydrexidine12 (1, Chart 1), the first high-affinity
D1-selective full agonist, demonstrated profound antiparkinso-
nian effects in an in vivo model of Parkinson’s disease in
African green monkeys,13 establishing the importance of
dopamine D1 receptor activation in the basal ganglia for the
control of motor function. Subsequent clinical trials with a
structurally related compound (ABT-431) demonstrated that D1
agonists were the only agents with efficacy in Parkinson’s
Dopamine D1 receptors also are thought to be a key target
for improving cognitive and working memory deficits in
* To whom correspondence should be addressed. Phone: 765-494-1461.
Fax: 765-494-1414. E-mail: drdave@pharmacy.purdue.edu.
† Current Address: Department of Chemical Sciences, University of
Camerino, Via S. Agostino, 1-62032 Camerino, Italy.
10.1021/jm0604979 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/17/2006

An Isoquinoline as Dopamine D1 Receptor Agonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6849
Scheme 1a
Chart 1
disease comparable to levo-dopa,14 the current “gold standard”
of treatment.
a Reagents and conditions: (a) (i) THF, nBuLi, -78 °C; (ii) isopro-
poxypinacolborane, room temp, 52%; (b) NaOH, Na2CO3, Br(CH2)2COOH,
H2O, reflux, 11%; (c) oxalyl chloride, SnCl4, benzene, 88%; (d) NaHMDS,
(CF3SO2)2NPh, THF, 80%; (e) 8, KBr, KOH, Pd(PPh3)4, 71%; (f) C(NO2)4,
pyridine, acetone, 91%.
The structure of dihydrexidine, 1, can be seen to incorporate
a conformation of dopamine where its ethylamine side chain is
held in the “trans-â” rotameric orientation by a tetracyclic ring
system that includes the catechol and â-phenyl moieties. The
trans relationship between the â-phenyl and the amino substitu-
ent establishes an energetically stable conformation in which
both aromatic groups of 1 are not far from coplanarity. These
basic structural features have been incorporated into a more
general dopamine D1 agonist pharmacophore that has been used
as a basis for the development of subsequent dopamine D1-
selective full agonists such as dinapsoline 2,15 which also is a
full D1 agonist.
Scheme 2a
The pursuit of an oxygen bioisostere of dinapsoline yielded
dinoxyline, 3, a potent dopamine agonist at all receptor
isoforms.16 Incorporation of other heteroatoms into the tether,
such as sulfur or nitrogen, did not afford active compounds.17
We were encouraged to expand our search for other oxygen
bioisosteres by the results of Horn et al.18 and of Hutchison et
al.,19 who reported that both 4 and 5 possessed significant
dopaminergic activity. Their successes using heteroatom re-
placement in known dopaminergic ligands, and analogies to our
structural series, convinced us to prepare 6, an analogue of 1 in
which the ethyl tether between the catechol and tetrahydroiso-
quinoline substructures was replaced with an oxymethylene ether
bridge. This new compound, trans-2,3-dihydroxy-6a,7,8,12b-
tetrahydro-6H-chromeno[3,4-c]isoquinoline, 6, which we have
tentatively named doxanthrine, its biological properties, and
those of its enantiomers are the subject of the present com-
munication.
a Reagents and conditions: (a) NaBH4, EtOH, 35%; (b) Zn, CH3COOH,
60 °C, 38%; (c) NaBH3CN, MeOH, 90%.
With Suzuki conditions described by Qandil et al.,23 8 and
12 were coupled and 13 was isolated in good yield. Treatment
of 13 with tetranitromethane produced nitroalkene 14 in
excellent yield.24 After successful reduction of the olefinic bond
of 14 with sodium borohydride (Scheme 2), the resulting trans
product 15 was treated with zinc dust in aqueous acetic acid,
as reported by Michaelides et al.25
Instead of producing the desired dihydroisoquinoline, how-
ever, only aromatized 16 was obtained. In view of this minor
setback, the intermediate olefin reduction was abandoned, and
nitroalkene 14 was reduced directly to isoquinoline 16. To our
great disappointment, however, reduction of this isoquinoline
with sodium cyanoborohydride yielded cis amine 17 as the only
isolable product.
Although we did not consider these difficulties insurmount-
able, given the very low yields of key intermediates early in
this route, as well as the hardships that became evident in
attaining the desired trans stereochemistry of the product, we
decided to develop a new synthetic approach, prompted by
awareness of the reactivity of nitroalkenes toward arylmetal
reagents.25 This more successful route is detailed in Scheme 3.
Aldehyde 18 was obtained by formylation of sesamol, 9.
Reaction conditions for this formylation had to be chosen
carefully, as the reaction was prone to provide substantial
amounts of a dimeric xanthydrol byproduct (Cueva and Nichols,
unpublished observation). The key intermediate, nitrochromene
19, was obtained in one step from aldehyde 18 following a very
Chemistry
We initially approached the construction of 6 through a key
Suzuki coupling between boronate ester 8 and triflate 12 as
shown in Scheme 1. The synthesis of coupling partner 8 was
completed in two steps from 2-bromobenzaldehyde. After
preparation of the cyclic acetal 7,20 treatment with n-butyllithium
was followed by addition of isopropoxypinacolborane.
Synthesis of coupling partner 12 began with propionic acid
10, which was obtained by O-alkylation of sesamol (9) with
3-bromopropionic acid. Unfortunately, this step gave extremely
low yields because of base-catalyzed reverse Michael addition,
which regenerates starting phenol 9.21,22 Treatment of 10 under
Friedel-Crafts conditions gave chromanone 11 in excellent
yield. Triflate 12 was then obtained from 11 following a
procedure described by Pal.20 The enolate was generated by
treatment with sodium hexamethyldisilazane and was trapped
with N-phenyltrifluoromethanesulfonimide.

6850 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23
CueVa et al.
Scheme 3a
Scheme 4a
a Reagents and conditions: (a) Cl2CHOCH3, SnCl4, CH2Cl2, reflux, 46%;
(b) 2-nitroethanol, dibutylamine, phthalic anhydride, toluene, reflux, 48 h,
61%; (c) Mg, THF, -78 °C, 72%; (d) (i) Zn, AcOH, 60 °C; (ii) 2 M HCl;
(iii) 2 M NaOH, 87%; (e) NaBH3CN, HCl, EtOH, 79%; (f) BCl3, CH2Cl2,
45%; (g) allyl bromide, K2CO3, acetone, 82%; (h) Pd/C, H2, EtOH, 73%.
a Reagents and conditions: a) R-(-)-R-methoxyphenylacetyl chloride,
CH2Cl2, silica column chromatography, 43% for 27, 46% for 28; (b)
LiEt3BH, THF, 94%; (c) BCl3, CH2Cl2, 81%.
convenient procedure developed by Dauzonne and Royer26 and
later refined by Neirabeyeh and co-workers,27 in which a basic
solution of the aldehyde is treated with nitroethene generated
in situ from nitroethanol. The concentration of this latter reagent
must be kept very low to avoid base-catalyzed polymerization
of nitroethene, which was nevertheless a byproduct of the
process. This nitroalkene proved to be a very efficient electro-
phile; its reaction with the Grignard reagent formed from
o-bromobenzaldehyde gave exclusively the more thermody-
namically stable trans nitroacetal 21. The reaction proceeded
in good yield with very easy product workup. Imine 22 was
then accessible by reduction of the nitro moiety of 21, followed
by acidic treatment to cleave the acetal and then basification.
The difference in outcome for the reduction of 15 and 21
with powdered Zn and acetic acid can likely be attributed to
the stability of the six-membered acetal moiety under acidic
conditions. The five-membered acetal 15 readily affords the
aldehyde upon treatment with acetic acid, whereas the six-
membered acetal 21 requires more stringent acidic conditions
to effect hydrolysis. Thus, the ring closure step for the reduction
of the five-membered acetal (which yields isoquinoline 16)
seems likely to have occurred by attack of a nitrogen nucleophile
in an oxidation state higher than the amine. The general behavior
of nitroalkenes to many reduction conditions is their transforma-
tion to oximes rather than amines.28 This speculation is
reinforced by the fact that 14 also yielded isoquinoline 16,
presumably by a ring closure step involving an oxidized nitrogen
species, likely an oxime. The nitro group in acetal 21 is first
reduced cleanly to the amine, and then after reaction conditions
are applied to unmask the intermediate aldehyde, cyclization
affords imine 22, allowing the trans stereochemistry of the ring
fusion to remain intact. Imine 22 was then reduced to yield the
racemic trans amine 23.
Figure 1. Crystal structure of (+)-23.
subsequent reductive cleavage of the amides using lithium
triethylborohydride29 afforded the enantiomers (+)-23 and (-)-
23.
The enantiomeric amines 23 gave crystals suitable for X-ray
crystallographic analysis. The structure of a crystal of the (+)-
enantiomer was determined to have the (6aR,12bS) stereochem-
istry (Figure 1). The catechol 6, doxanthrine hydrochloride, was
finally obtained by treatment of 23 with boron trichloride,
followed by recrystallization from EtOH/EtOAc. We also
prepared the N-propyl derivative by treatment of racemic amine
23 with allyl bromide to give 24, followed by catalytic reduction
to afford N-propyl compound 25 and conversion into catechol
26 by treatment with boron trichloride and crystallization as its
hydrochloride salt.
The resolution of (()-23 employed separation of diastereoi-
someric amide derivatives 27 and 28, formed by treatment of
(()-23 with R-(-)-O-methylmandeloyl chloride (Scheme 4).
The amides were separated by column chromatography, and
Pharmacology
The dopamine D1-like and D2-like receptor affinities of
compounds (()-6, (+)-6, (-)-6, and (()-26 were initially

An Isoquinoline as Dopamine D1 Receptor Agonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6851
Figure 2. Representative competition binding curves for compounds
26, 6, and the enantiomers of 6 were obtained at D1-like receptors in
porcine striatal membranes. The prototype antagonist SCH-23390 is
included for comparison.
Figure 4. Stimulation of cAMP in HEK hD1 CRE-Luc cells by
compounds (()-6, (+)-6, (-)-6, and 26. The 100% represents the
maximal effect produced by 10 µM dopamine. Data represent mean (
SEM from at least four experiments.
Although the basis for this difference in affinity is unclear, we
note that SER107 in the D1 receptor is located in the vicinity
of the oxygen heteroatom in 6. This residue is located ap-
proximately one turn below the critical ASP103 in transmem-
brane helix 3 that is thought to bind to the amine of dopamine.
The cognate residue in the D2 receptor is a cysteine, and it seems
likely that hydrogen bonding of the ether oxygen atom in 6
will be more favorable with SER in the dopamine D1 receptor
than with the CYS in the dopamine D2 receptor. Experiments
to test this hypothesis are now underway.
We then submitted (()-6 to the NIMH sponsored Psycho-
active Drug Screening Program (NIMH-PDSP). Compound
(()-6 had no significant affinity (>10 µM) at the panel of
monoamine targets, with only the few exceptions that are listed
in Table 2. These assays also revealed (()-6 to have affinity at
the dopamine D4 receptor (Ki ) 90 nM) and at the D5 receptor,
where it had affinity (Ki ) 7 nM) comparable to that at the D1
receptor. We are presently examining the dopamine D5 proper-
ties of 6 to determine whether the high affinity reported by the
NIMH-PDSP is an indication of whether 6 may have measurable
selectivity for D5 over D1 receptors.
As anticipated, the enantiomers of 6 showed the affinity
difference predicted by analogy to earlier examples of resolved
â-phenyl substituted catecholamines: that is, the (6aS,12bR)-
(+)-enantiomer of 6 was most potent, with more than twice
the affinity of the racemate at dopamine D1 receptors (7 nM vs
22 nM for (()-6) and 40-fold higher affinity than the distomer
(290 nM for (-)-6).
Figure 3. Representative competition binding curves for compounds
26, 6, and the enantiomers of 6 at D2-like receptors in porcine striatal
membranes. The prototype antagonist chlorpromazine (CPZ) is included
for comparison.
evaluated by a competitive binding assay using a porcine striatal
tissue preparation. Standard ligands for D1- and D2-type
receptors, SCH 23390 and chlorpromazine, were assessed for
comparison. Competitive binding at all five dopamine receptors
and for adrenergic receptors was carried out by the NIMH
supported Psychoactive Drug Screening Program.
To establish the functional effects of these compounds at
specific receptor isoforms, we employed standard cAMP
quantification assays using stably transfected cell lines express-
ing cloned dopamine D1, D2, and D4 receptors. Full intrinsic
activity was defined as the maximal activation induced by the
endogenous neurotransmitter dopamine.
It has been consistently observed that addition of an N-propyl
to most dopaminergic agonists tends to increase affinity and
potency at D2-like receptors while simultaneously reducing the
affinity for D1-like receptors, resulting in a net change in
selectivity favoring D2 activity.12,16,23 With dihydrexidine 1, for
example, an N-propyl effectively increased the affinity of the
compound for D2 receptors by 2-fold. The net effect of the
N-propyl in this new template was similar: although N-propyl
analogue 26 had only modest affinity at D2-like receptors (Ki
) 300 nM), compared to its parent (()-6, the increase in affinity
was substantial (about 10-fold). The decrease in D1 affinity was
also considerable (from 22 nM for 6 to 340 nM for 26), but the
low D2 affinity of the N-unsubstituted template made it
impossible for N-alkylation to provide a D2-selective compound,
as is the case with structurally related molecules.
Results and Discussion
The receptor-binding and functional properties of these new
compounds at dopamine receptors are presented in Figures 2-4
and are summarized in Tables 1 and 2. In our competition
binding assays using porcine striatal preparations, we show the
racemic parent compound (()-6 (doxanthrine) to have high
affinity (Ki ) 22 ( 3 nM) at D1-like receptors (D1 and D5),
comparable to the affinity of dihydrexidine 1. It should be noted
that cleavage of the dioxole ring of the cis ring fused isomer
17 gave a catechol that did not have measurable affinity for
D1- or D2-like receptors (data not shown), similar to our earlier
finding with cis-1.12
We were quite surprised to discover, however, that in this
assay, (()-6 had only very low affinity (Ki ) 3000 nM) at D2-
type receptors, in sharp contrast to the carbocyclic analogue,
dihydrexidine 1, which does possess modest D2-like affinity (Ki
) 240 nM). These observations reveal high selectivity toward
D1-type over D2-type receptors for this new molecular template.
Functionally, (()-6 was a potent agonist at dopamine D1
receptors, with full intrinsic activity relative to dopamine. The
(+)-isomer was slightly more potent than the racemate in this
assay (EC50 ) 29 nM) but induced a very robust activation of

6852 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23
CueVa et al.
Table 1. Binding and Functional Properties of New Compounds at Dopamine Receptorsa
potency (nM) and intrinsic activity at cloned receptors
hD1 rD2L
binding at porcine striatal homogenates, Ki (nM)
D1-like D2-like
NDc NDc
hD4.4
IAb
ligand
EC50
IAb
EC50
5 ( 2
70 ( 20
IAb
EC50
dopamine
1, DHXd
(()-6
120 ( 20
19 ( 8
32 ( 19
29 ( 11
1100 ( 360
1100 ( 460
NDc
100 ( 3
110 ( 11
95 ( 3
130 ( 10
87 ( 3
88 ( 2
N.D
100 ( 2
70 ( 5
nae
10 ( 2
17 ( 3
110 ( 15
95 ( 25
230 ( 90
21 ( 8
NDc
100 ( 2
100 ( 7
87 ( 3
90 ( 4
80 ( 5
100 ( 3
NDc
21 ( 4
22 ( 3
8 ( 3
270 ( 30
330 ( 50
180 ( 11f
NDc
240 ( 40
3700 ( 1300
2500 ( 820
6800 ( 660
340 ( 40
26 ( 3f
>10 µM
(+)-6
>10 µM
>10 µM
nae
(-)-6
nae
26
1600 ( 100
92 ( 3
N-propyl-1
quinpirole
SCH-23390
chlorpromazine
NDc
NDc
NDc
NDc
NDc
9 ( 2
95 ( 2
nae
5 ( 1
100 ( 3
0.5 ( 0.1
NDc
nae
nae
nae
nae
nae
nae
NDc
8 ( 2
nae
nae
nae
nae
nae
a All results shown are the mean ( SEM for at least three independent experiments. b IA is intrinsic activity, the maximum stimulation observed relative
to the response of dopamine, which is defined as 100% intrinsic activity. c Not determined by these assays. d Dihydrexidine. e Not applicable for antagonists.
f Taken from Knoerzer et al.29 from rat striatal homogenates.
Table 2. Affinity of (()-6 for Cloned Human Receptor Subtypesa
monitor reactions. Melting points were determined using a Thomas-
Hoover apparatus and are uncorrected. 1H NMR spectra were
receptor
recorded using a 300 MHz Bruker ARX-300 NMR spectrometer.
D1
98
D2
D3
D4
90
D5
7
R2A
R2B
R2C
Chemical shifts are reported in δ values in ppm relative to an
internal reference (0.03%, v/v) of tetramethylsilane (TMS) in CDCl3
except where noted. All electrospray ionization analyses were
carried out on a FinniganMAT LCQ Classic (ThermoElectron Corp,
San Jose, CA) mass spectrometer system. The low-resolution
electron impact (EI) and chemical ionization (CI) studies were
carried out using a Hewlett-Packard Engine (Hewlett-Packard
Company, Wilmington, DE) mass spectrometer. Elemental analyses
were performed by the Purdue University Microanalysis Laboratory.
All reactions were carried out under an argon atmosphere.
Ki (nM)
1910
390
180
10
2
a Screening data provided by the NIMH-sponsored PDSP. D1 and
D5 data represent an average of two trials. All other data represent a
single trial.
the D1 receptor, with an intrinsic activity about 30% greater
than that of dopamine itself! The (-)-isomer was a weak agonist
(EC50 ) 1100 nM) but still had nearly full intrinsic activity at
the highest concentrations tested.
2-(2-[1,3]Dioxolan-2-ylphenyl)-4,4,5,5-tetramethyl[1,3,2]-
dioxaborolane (8). The protected aldehyde 720 (22.8 g, 0.100 mol)
was dissolved in 400 mL of dry THF. After the solution was cooled
to -78 °C, a 2.5 M solution of n-butyllithium (44.0 mL, 0.110
mol) was added. After 15 min, 2-isopropoxy-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (22.4 mL, 0.110 mol) was added. The solution
was allowed to warm to room temperature and was stirred for an
additional 8 h. The resulting mixture was poured into 300 mL of
water, extracted several times with diethyl ether (3 × 300 mL),
dried (Na2SO4), filtered, and concentrated. The resulting oil (14.4
The potency of (()-6 and its enantiomers at dopamine D2
receptors was negligible (EC50 > 10 µM). Although the
N-propyl analogue 26 had low but nearly equal EC50 values
for both D1 and D2 receptor activation, it nevertheless was a
nearly full agonist at the highest concentration tested.
The functional effects of these compounds at dopamine D4
receptors are particularly noteworthy. Racemic 6 had only
modest potency at dopamine D4 receptors (EC50 ) 110 nM),
about 10-fold lower than its isosteric predecessor, (()-dihy-
drexidine (EC50 ) 17 nM) (Table 1). But when the N-propyl
was added to provide 26, we observed a 5-fold increase in D4
potency (EC50 ) 21 nM). Combined with the marked loss of
D1 and nearly 20-fold lower D2 potency, 26 thus appears to be
a relatively selective dopamine D4 full agonist.
1
g, 52%) was used without further purification. H NMR (CDCl3):
δ 7.71 (d, 1H, J ) 7.2 Hz), 7.59 (d, 1H, J ) 8.1 Hz), 7.40 (m,
2H), 6.35 (s, 1H), 4.10 (m, 2H), 4.00 (m, 2H), 1.34 (s, 12H).
3-(3,4-Methylenedioxyphenoxy)propionic Acid (10). Sesamol
9 (50 g, 0.36 mol) was treated with an aqueous sodium hydroxide
solution prepared from 500 mL of H2O and 14.5 g (0.36 mol) of
NaOH pellets. To an aqueous suspension (250 mL) of 3-bromopro-
pionic acid (55.07 g, 0.36 mol), 250 mL of an aqueous sodium
carbonate (38.16 g, 0.36 mol) solution was slowly added. The two
solutions were combined and the mixture was then heated at reflux
for 16 h. After the mixture was cooled to room temperature, ice
(200 g) was added. The solution was acidified with concentrated
HCl and extracted with diethyl ether (3 × 350 mL). The organic
extracts were combined and then extracted with an aqueous
saturated NaHCO3 solution (3 × 400 mL). The basic aqueous
extracts were acidified with concnetrated HCl and extracted back
into diethyl ether (3 × 400 mL). The ethereal extracts were dried
(Na2SO4) and concentrated, and the title compound was recrystal-
lized as tan crystals from 80% aqueous ethanol (8.16 g, 11%). The
reaction was repeated several times to accumulate sufficient material
to complete the synthesis. An analytical sample was prepared by
dissolving the crystals in hot ethanol, treating with charcoal followed
by filtration through Celite, and cooling to afford white crystals
that were collected by filtration: mp 144-146 °C. 1H NMR
(DMSO-d6): δ 6.78 (d, 1H, J ) 8.4 Hz), 6.60 (d, 1H, J ) 3 Hz),
6.34 (dd, 1H, J ) 8.7, 3 Hz), 5.94 (s, 2H), 4.06 (t, 2H, J ) 6 Hz),
2.63 (t, 2H, J ) 6 Hz). Low-resolution EIMS m/z: 210. Anal.
(C10H10O5) C, H, N.
Conclusions
We have devised an efficient synthesis for the construction
of a new conformationally restricted version of the â-phenyl-
dopamine pharmacophore. In doing so, we have been successful
in producing a ligand that we have named doxanthrine 6, which
possesses a level of D1/D2 selectivity never before encountered
for a conformationally rigid full agonist. In view of its
pharmacological properties and its isosteric relationship with
dihydrexidine 1, it provides opportunities to identify key residues
involved in the differential ligand-receptor interactions that give
rise to isoform selectivity.
Experimental Section
Chemistry. General Procedures. All reagents were com-
mercially available (Aldrich) and were used without further
purification unless otherwise indicated. Dry THF and diethyl ether
were obtained by distillation immediately before use from ben-
zophenone-sodium under nitrogen. Column chromatography was
carried out using silica gel 60 (230-400 mesh). J. T. Baker flexible
thin layer chromatography sheets (silica gel IB2-F) were used to

An Isoquinoline as Dopamine D1 Receptor Agonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6853
6,7-Methylenedioxychroman-4-one (11). A catalytic amount of
dry DMF was added to a suspension of 10 (20.4 g, 0.097 mol) in
500 mL of dry benzene. Oxalyl chloride (16.7 mL, 0.191 mol) was
then added, and the resulting solution was stirred at room
temperature for 4 h. The benzene was then removed under reduced
pressure, and the resulting oil was dissolved in 300 mL of dry
dichloromethane. After the solution was cooled to 0 °C, SnCl4
(13.58 mL, 0.12 mol) was added and the solution was stirred for 1
h while allowing it to warm to room temperature. After the reaction
mixture was poured onto ice (200 g) and after dilution with water
(300 mL), the aqueous layer was extracted with dichloromethane
(3 × 300 mL). The organic extracts were dried (Na2SO4), filtered,
and concentrated under vacuum. The resulting solid was dissolved
in 1 L of 50% hexanes-ethyl acetate, passed through a small pad
of silica gel, and concentrated to afford a tan solid that was
recrystallized from ethanol (16.4 g, 88%). An analytical sample
was prepared by dissolving the solid in hot ethanol, treatment with
charcoal, filtration through Celite, and cooling to give white needles
that were collected by filtration: mp 92-93 °C. 1H NMR
(CDCl3): δ 7.25 (s, 1H), 6.41 (s, 1H), 5.97 (s, 2H), 4.46 (t, 2H, J
) 6 Hz), 2.72 (t, 2H, J ) 6 Hz). EIMS m/z: 192. Anal. (C10H8O4)
C, H, N.
(CDCl3): δ 7.64 (m, 1H), 7.45 (m, 2H), 7.10 (m, 1H), 6.50 (s,
1H), 6.07 (s, 1H), 5.91 (s, 2H), 5.61 (s, 1H), 5.22 (d, 2H, J ) 6.3
Hz), 3.97 (m, 1H), 3.89 (m, 1H), 3.85 (m, 2H). EIMS m/z: 369.
Anal. (C19H15NO7) C, H, N.
2,3-Methylenedioxy-6H-5-oxa-7-aza-benzo[c]phenan-
thracene (16). Nitrochromene 14 (1.5 g, 4.10 mmol) was suspended
in 80 mL of aqueous acetic acid (3:1, AcOH-H2O). After addition
of Zn dust (3.05 g, 41.0 mmol), the mixture was heated at 60 °C
for 30 min. The majority of the acetic acid was then removed by
rotary evaporation, and the remaining acid was neutralized by
adding a saturated aqueous solution of NaHCO3. The aqueous layer
was extracted several times with dichloromethane (3 × 350 mL),
dried (Na2SO4), filtered, and concentrated. The amine was then
purified by column chromatography (silica gel, 50% ethyl acetate-
hexanes) and recrystallized from ethyl acetate as lime-colored
needles (0.43 g, 38%). The same product was recovered when 15
was subjected to the Zn/HCl reduction conditions reported by
1
Michaelides et al.:25 mp 176-177 °C. H NMR (CDCl3): δ 9.03
(s, 1H), 8.45 (d, 1H, J ) 9 Hz), 8.00 (d, 1H, J ) 9 Hz), 7.74 (t,
1H, J ) 3 Hz), 7.60 (t, 1H, J ) 3 Hz), 7.46 (s, 1H), 6.72 (s, 1H),
6.02 (s, 2H), 5.20 (s, 2H). CIMS m/z: 278. Anal. (C17H11NO3) C,
H, N.
6,7-Methylenedioxy-4-trifluoromethanesulfonyl-2H-
chromene (12). With conditions described by Pal,19 11 (8.7 g, 0.045
mol) was dissolved in 300 mL of dry THF and cooled to -78 °C,
and 50 mL of a sodium bis(trimethylsilyl)amide solution (1.0 M
in THF, 0.050 mol) was added. The solution was stirred for 1 h at
-78 °C. N-Phenyltrifluoromethanesulfonimide (17.86 g, 0.050 mol)
dissolved in 50 mL of dry THF was then added to the enolate
solution via syringe, and the mixture was stirred for 1 h while
warming to room temperature. After the reaction was quenched
with 300 mL of brine, the product was extracted into ethyl acetate
(3 × 300 mL), dried (Na2SO4), concentrated, and purified by flash
chromatography (silica gel, 95% hexanes-ethyl acetate) to yield a
yellow oil (11.66 g, 80%) that was used immediately in the next
step. 1H NMR (CDCl3): δ 6.71 (s, 1H), 6.42 (s, 1H), 5.94 (s 2H),
5.61 (t, 1H, J ) 4.2 Hz), 4.86 (d, 2H, J ) 4.2 Hz). EIMS m/z:
324.
(()-cis-2,3-Methylenedioxy-6a,7,8,12b-tetrahydro-6H-5-oxa-
7-azabenzo[c]phenanthracene (17). Phenanthracene 16 (0.582 g,
2.1 mmol) was suspended in 100 mL of methanol. Powdered
sodium cyanoborohydride (0.80 g, 12.7 mmol) was then added to
the solution in a single portion, and a few crystals of bromocresol
green were added. A 10% methanolic HCl solution was added
dropwise to the blue solution until a yellow color persisted.
Additional methanolic HCl was added periodically to maintain a
slightly acidic solution. The mixture was then stirred overnight.
When the reaction was complete, the methanol was removed by
rotary evaporation. The resulting oil was dissolved in 250 mL of
water, made basic with 2 N NaOH, extracted with dichloromethane
(3 × 250 mL), dried (Na2SO4), filtered, and concentrated. The
resulting oil was dissolved in 25 mL of diethyl ether and
concentrated to afford a tan solid (0.531 g, 90%). 1H NMR
(CDCl3): δ 7.21 (m, 3H), 7.01 (d, 1H, J ) 6 Hz), 6.56 (s, 1H),
6.33 (s, 1H), 5.75 (d, 2H, J ) 15 Hz), 4.21 (d, 2H, J ) 3 Hz), 4.05
(q, 2H, J ) 18 Hz), 3.89 (d, 1H, J ) 6 Hz), 3.29 (q, 1H, J ) 3
Hz). CIMS m/z: 282. Anal. (C17H15NO3) C, H, N.
6,7-Methylenedioxy-4-(2-[1,3]dioxolan-2-ylphenyl)-2H-
chromene (13). Triflate 12 (11.86 g, 0.036 mol), after purification,
was immediately dissolved in 100 mL of dry toluene. The pinacol
boronate ester 8 (14.4 g, 0.052 mol), potassium bromide (12.85 g,
0.108 mol), potassium hydroxide (6.10 g, 0.108 mol), and tetrakis-
(triphenylphosphine)palladium(0) (2.1 g, 5 mol %) were suspended
in 50 mL of dry toluene and combined with the triflate solution.
The mixture was degassed by bubbling argon through for 15 min
and was then heated at reflux for 1 h. After the mixture had been
cooled to room temperature, 200 mL of water was added and the
aqueous layer was extracted with toluene (3 × 200 mL). The
organic extracts were combined, dried (Na2SO4), filtered, and
concentrated. The resulting black oil was purified by column
chromatography (silica gel, 80% hexanes-ethyl acetate) to afford
a white solid (8.2 g, 71%). An analytical sample was recrystallized
6-Hydroxybenzo[1,3]dioxole-5-carboxaldehyde (18). Sesamol
9 (50.98 g, 369 mmol) was dissolved in 600 mL of CH2Cl2,
followed by 52 mL (448 mmol) of SnCl4, and the solution was
cooled to 0 °C. Cl2CHOCH3 (35 mL, 387.5 mmol) was then added
dropwise as the mixture warmed to room temperature and was
stirred for 3 h. The mixture was poured over ice, and the water
layer was separated and extracted once with CH2Cl2 (30 mL). The
organic extracts were pooled, washed with 2 M HCl (5 × 100 mL)
to remove tin salts, brine (50 mL), and was then passed through a
small column packed with MgSO4, which removed color. The
solvent was then removed under reduced pressure to yield 28 g
(46% yield) of pure aldehyde as a cream-colored powder: mp 119
1
1
from ethyl acetate-hexane: mp 126-127 °C. H NMR (CDCl3):
°C. H NMR (CDCl3): δ 9.63 (s, 1H, CHO), 6.87 (s, 1H, ArH),
δ 7.66 (dd, 1H, J ) 7.5, 2.1 Hz), 7.38 (td, 2H, J ) 9, 2.1 Hz), 7.14
(dd, 1H, J ) 9.0, 2.1 Hz), 6.70 (s, 1H), 6.44 (s, 1H), 6.13 (s, 1H),
5.83 (s, 2H), 5.71 (s, 1H), 5.63 (t, 1H, J ) 3.9 Hz), 4.80 (d, 1H, J
) 3.9 Hz), 4.12 (m, 2H), 3.92 (t, 2H, J ) 5.7 Hz). EIMS m/z:
324. Anal. (C19H16O5) C, H, N.
6,7-Methylenedioxy-4-(2-[1,3]dioxolan-2-ylphenyl)-3-nitro-
2H-chromene (14). Following the procedure described by Shul-
gin,24 13 (3.3 g, 102 mmol) and 0.85 mL (105 mmol) of pyridine
were dissolved in 100 mL of acetone and the solution was cooled
to 0 °C. Tetranitromethane (1.3 mL, 106 mmol) was then added,
and the solution was stirred for 5 min. The reaction was quenched
by adding 100 mL of 1.0 M KOH and stirring the resulting orange
mixture for 30 min at 0 °C. The aqueous layer was extracted with
ethyl ether (3 × 250 mL), dried (Na2SO4), filtered, and concentrated.
The nitrochromene 14 was obtained by flash chromatography (silica
gel, 50% hexanes-ethyl acetate) and recrystallized from methanol
as bright-orange needles (3.43 g, 91%): mp 129-131 °C. 1H NMR
6.47 (s, 1, ArH), 6.02 (s, 2H, ArOCH2O), 1.54 (s, 1H, ArOH).
Low-resolution CIMS: m/z (relative intensity) 167 (MH+, 100).
Anal. (C8H6O4) C, H, N.
7-Nitro-6H-[1,3]methylenedioxy[4,5-g]chromene (19). Alde-
hyde 18 (6 g, 36.14 mmol) was dissolved in 300 mL of toluene
containing 3.1 mL of dibutylamine (18.16 mmol) and 10.72 g (72.37
mmol) of phthalic anhydride in a two-necked flask equipped with
a Dean-Stark trap, a condenser, and an addition funnel. The
solution was heated to reflux, and nitroethanol (7 mL 97.69 mmol)
was added very slowly over 18 h (∼1 drop every 10 min) while
vigorously stirring. After addition was complete, the mixture was
stirred at reflux for an additional 24 h. The flask was then cooled
to room temperature, the reaction mixture was filtered through
Celite, and the filtrate was washed with 2 M NaOH (3 × 300 mL),
brine (100 mL), and then dried over MgSO4. After filtration, the
organic solution was concentrated under reduced pressure and the
crude concentrated solution was passed through a short column of

6854 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23
CueVa et al.
silica to remove dark polar impurities. This eluate was then
concentrated under vacuum, and the residue was recrystallized from
methanol to afford 4.89 g (61% yield) of pure nitrochromene 19
Jvic ) 5.1 Hz, Jgem ) 10.2 Hz), 4.24 (s, 1H, ArCH2N), 4.09 (t, 1H,
OCH2, Jgem ) 10.2 Hz), 4.03 (d, 1H, ArCHAr, Jtrans ) 11.4 Hz),
3.12 (dt, 1H, NCH, Jtrans) 11.4 Hz, Jvic ) 5.1 Hz). Low-resolution
CIMS: m/z (relative intensity) 282 (MH+, 100). Anal. (C17H15-
NO3) C, H, N.
1
as bright-red needles: mp 139 °C. H NMR (CDCl3): δ 5.20 (s,
2H, ArOCH2), 6.02 (s, 2H, OCH2O), 6.49 (s, 1H, ArH), 6.69 (s,
1H, ArH), 7.75 (s, 1H, ArCH). Low-resolution CIMS: m/z (relative
intensity) 222 (MH+, 100). Anal. (C10H7NO5) C, H, N.
(()-2,3-Dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-
c]isoquinoline hydrochloride ((()-6). Amine 23 (570 mg, 2.03
mmol) was dissolved in 40 mL of CH2Cl2, and the solution was
cooled to -78 °C. BCl3 (8.1 mL of 1 M solution, 8.1 mmol) was
added through a syringe, and the solution was allowed to warm to
0 °C and then stirred for 4 h. MeOH (20 mL) was added to quench
the reaction, and the mixture was stirred for another hour. The
solvents were then removed under vacuum, MeOH was again added,
and the solution was concentrated to yield the product in quantitative
yield and pure by NMR. Recrystallization from MeOH and then
drying under vacuum at 70 °C yielded 280 mg of crystalline 6 as
an off-white powder (45% yield): mp 185-190 °C (dec). 1H NMR
(D2O): δ 7.55-7.43 (m, 4H, Ar), 7.07 (s, 1H, ArH), 6.61 (s, 1H,
ArH), 4.60 (dd, 1H, ArOCH2), 4.55 (2d, 2H, ArCH2N, J ) 7 Hz),
4.34 (d, 1H, ArCHAr, J ) 11.5 Hz), 4.20 (t, 1H, ArOCH2, J ) 10
Hz), 3.35 (dt, 1H, NCH, Jtrans ) 11.5 Hz, J2 ) 4.2 Hz).
Low-resolution ESIMS: m/z (relative intensity) 270 (MH+, 100).
Anal. (C16H15NO3‚H2O‚HCl) C, H, N.
(()-trans-6,7-Methylenedioxy-3-nitro-4-(2-[1,3]dioxan-2-ylphe-
nyl)-3,4-dihydro-2H-chromene (21). Acetal 2020 (9.04 g, 37.22
mmol) was dissolved in 50 mL of dry THF under an inert
atmosphere in a two-necked flask equipped with a condenser.
Magnesium powder (1.8 g, 74.44 mmol) was added to the flask,
and the mixture was stirred at 80 °C for 45 min to form the Grignard
reagent. The flask was then cooled to room temperature, and a
solution of 2.74 g (12.41 mmol) of nitrochromene 19 in 50 mL of
THF was cannulated into the Grignard reagent. After stirring for
30 min, water was added to quench the reaction. The mixture was
then extracted with CH2Cl2 (3 × 100 mL), the extracts were washed
with brine (100 mL), dried over MgSO4, filtered, and stripped of
solvent, yielding a brown oil from which product spontaneously
crystallized. The crystals were collected by filtration, rinsed on the
filter with 30 mL of cold EtOAc, and dried to afford 2.91 g (61.4%)
of a homogeneous cream-colored powder. Additional material was
obtained from the mother liquor by flash column chromatography
to provide 550 mg (72% overall yield) of product: mp 207 °C. 1H
NMR (CDCl3): δ 7.50 (m, 1H, ArH), 7.29 (m, 2H, ArH), 6.99
(m, 1H, ArH), 6.47 (s, 1H, ArH), 6.38 (s, 1H, ArH), 5.90 (d, 2H,
ArOCH2), 5.70 (s, 2H, OCH2O), 4.97 (s, 1H, O2CHAr), 4.71 (dq,
1H, Ar2CH, J ) 10 Hz), 4.23 (m, 2H + 1H, CH2(CH2O)2, CHNO2),
3.98 (m, 2H CH2(CH2O)2), 2.22 (m, 1H, CH2), 1.43 (d, 1H, CH2).
Low-resolution CIMS: m/z (relative intensity) 386 (MH+, 100).
Anal. (C20H19NO7) C, H, N.
(()-trans-2,3-Methylenedioxy-6a,12b-dihydro-6H-chromeno-
[3,4-c]isoquinoline (22). Acetal 21 (1.84 g, 4.77 mmol) was
dissolved in a mixture of 70 mL of THF and 30 mL of AcOH.
Zinc dust (1.9 g, 30 mmol) was added through a powder funnel,
and the mixture was stirred for 3 h on an oil bath at 70 °C under
a reflux condenser. The mixture was then cooled and filtered, and
the solid metal and salts on the filter were rinsed with warm THF.
The filtrate was concentrated to dryness, and the residue was stirred
in 50 mL of 2 M ethanolic HCl at room temperature for 1 h to
deprotect the aldehyde. The solvents were then evaporated under
reduced pressure, and an amount of 100 mL of 2 M NaOH was
added. The mixture was then vigorously stirred with 150 mL of
CH2Cl2 for 1 h. The organic layer was recovered, and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated
to dryness. The residual solid was recrystallized from EtOH to yield
1.16 g (87%) of pure imine as white needles: mp 191 °C. 1H NMR
(CDCl3): δ 8.43 (s, 1H, NCH), 7.65 (d, 1H, ArH), 7.47-7.34 (m,
3H, ArH), 6.95 (s, 1H, ArH), 6.51 (s, 1H, ArH), 5.94 (2d, 2H,
ArOCH2O), 4.63 (dd, 1H, ArOCH2 Jgem ) 10.4 Hz, Jvic ) 4.2 Hz),
4.08 (t, 1H, ArOCH2, Jgem ) 10.4 Hz), 3.80 (d, 1H, ArCH, J )
14.6 Hz), 3.45 (dt, 1H, CHN, J ) 14.6 Hz, Jvic ) 4.2 Hz). Low-
resolution CIMS: m/z (relative intensity), 280 (MH+, 100). Anal.
(C17H13NO3) C, H, N.
(()-trans-6-Allyl-5,6a,7,13b-tetrahydro-6H-[1,3]methylenedioxy-
[6,7]chromeno[3,4-c]isoquinoline (24). Amine 23 (300 mg, 1.067
mmol) was dissolved in 20 mL of dry acetone in a round-bottom
flask. Allyl bromide (0.11 mL, 1.281 mmol) and 220 mg (1.60
mmol) of K2CO3 were added to the flask, and the mixture was
stirred at room temperature for 12 h. The mixture was then filtered,
the volatiles were removed under reduced pressure, and the crude
material was redissolved in 20 mL of CH2Cl2. The organic solution
was washed once with 5 mL of H2O, dried over Na2SO4, and
filtered, and the solvent was removed under reduced pressure. The
crude material was recrystallized from EtOH to yield 281 mg (82%
1
yield) of the free base as colorless crystals: mp 97 °C. H NMR
(DMSO-d6): δ 7.23-7.30 (m, 4H, Ar), 6.89 (s, 1H, ArH), 6.56 (s,
1H, ArH), 5.98 (d, 2H, OCH2O), 6.80 (m, 1H, vinylic), 5.15 (m,
2H, gem vinylic), 4.32 (dd, 1H, ArOCH2, Jgem ) 10.2 Hz, Jvic
)
4.2 Hz), 3.99 (d, 1H, ArCHAr, Jtrans ) 11.4 Hz), 3.97 (d, 1H,
ArCH2N, Jgem )15 Hz), 3.78 (t, 1H, ArOCH2, Jgem ) 10.2 Hz),
3.64 (d, 1H, ArCH2N, Jgem ) 15 Hz), 3.18 (dd, 1H, allylic), 2.91
(dd, 1H, allylic), 2.22 (dt, 1H, NCH, Jtrans ) 11.4 Hz, Jvic ) 4.2
Hz). Anal. (C20H19NO3) C, H, N.
(()-trans-6-Propyl-5,6a,7,13b-tetrahydro-6H-[1,3]dioxolo[6,7]-
chromeno[3,4-c]isoquinoline (25). Amine 24 (100 mg, 0.311
mmol) was dissolved in 40 mL of EtOH, 10 mg of 10% Pd/C was
added, and the suspension was shaken under 30 psi of H2 for 4 h,
at which point H2 uptake had ceased. The catalyst was removed
by filtration, and the filtrate was concentrated. The crude residue
was recrystallized from EtOH to yield 73 mg (73% yield) of the
desired N-propyl analogue 25 as an off-white solid: mp 119 °C.
1H NMR (DMSO-d6): δ 7.23-7.30 (m, 4, Ar), 6.89 (s, 1H, ArH),
6.56 (s, 1H, ArH), 5.98 (d, 2H, OCH2O), 4.27 (dd, 1H, ArOCH2
Jgem ) 10.2 Hz, Jvic ) 4.2 Hz), 3.96 (d, 1H, ArCH2N, Jgem )15
Hz), 3.94 (d, 1H, ArCHAr, Jtrans ) 11.4 Hz), 3.76 (t, 1H, ArOCH2,
Jgem ) 10.2 Hz), 3.63 (d, 1H, ArCH2N, Jgem ) 15 Hz), 2.34 (m,
2H, NCH2), 2.18 (dt, 1H, NCH, Jtrans ) 11.4 Hz, Jvic ) 4.2 Hz),
1.44 (m, 2H, CCH2C), 0.84 (t, 3H, CH3). CIMS: m/z (relative
intensity) 324 (MH+, 100). Anal. (C20H21NO3) C, H, N.
(()-trans-2,3-Dihydoxy-7-propyl-6a,7,8,12b-tetrahydro-6H-
chromeno[3,4-c]isoquinoline Hydrochloride (26). N-Propylamine
25 (50 mg, 0.154 mmol) was dissolved in 10 mL of CH2Cl2 and
cooled to -78 °C. A solution of 1 M BCl3 (0.46 mL) was then
introduced through a syringe. The solution was allowed to warm
to room temperature overnight and was then cooled to 0 °C and
quenched with 1 mL of dry MeOH. This solution was stirred for
30 min, and the solvents were removed under reduced pressure.
Dry MeOH (2 mL) was added, and the solvents were again removed
under reduced pressure. This procedure was repeated once more,
and the crude mixture was recrystallized from EtOH to yield 39
mg (72% yield) of the title compound as a cream-colored powder:
(()-trans-2,3-Methylenedioxy-6a,7,8,12b-tetrahydro-6H-
chromeno[3,4-c]isoquinoline (23). Imine 22 (1.16 g, 4.15 mmol)
was dissolved in 250 mL of a 60:30 mixture of EtOH-THF.
NaBH3CN (261 mg, 4.15 mmol) was then added with stirring until
it dissolved. The mixture was maintained at acidic pH by addition
of 2.1 mL of 2 M ethanolic HCl in four portions while the mixture
was stirred for 4 h. The solution was then reduced to one-fourth
its volume and made basic with NaOH. Excess water was added,
and the mixture was extracted with CH2Cl2 (3 × 50 mL). The
extracts were washed with brine, and the organic phase was dried
over MgSO4. After filtration, the solvent was removed and the
residual solid was recrystallized from ethanol to yield 0.922 g (79%)
of the amine as colorless needles: mp 188 °C. 1H NMR (CDCl3):
δ 7.48 (d, 1H, ArH), 7.35-7.25 (m, 3H, ArH), 6.91 (s, 1H, ArH),
6.53 (s, 1H, ArH), 5.95 (s, 2H, ArOCH2O), 4.47 (dd, 1H, ArOCH2,

An Isoquinoline as Dopamine D1 Receptor Agonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6855
1
mp 230-245 °C (dec). H NMR (DMSO-d6): δ 9.21 (s br, 1H,
(6aR,12bS)-(+)-2,3-Dihydroxy-6a,7,8,12b-tetrahydro-6H-
chromeno[3,4-c]isoquinoline Hydrochloride ((+)-6). A procedure
identical to the one used above for (()-6 but starting with (+)-23
OH), 8.41 (s br, 1H, OH), 7.53 (d, 1H, ArH), 7.47-7.37 (m, 3H,
ArH), 6.82 (s, 1H, ArH), 6.40 (s, 1H, ArH), 4.67-4.47 (m, 3H,
ArCHN, ArCH2N, OCH2), 4.37 (d, 1H, ArCHAr, Jtrans ) 11.4 Hz),
4.25 (t, 1H, OCH2, Jgem ) 10.5 Hz), 3.23-2.93 (m, 3H, NCH2,
NCH), 1.76 (m br, 2H, CH2CH3), 0.89 (t, 3H, CH3). ESIMS: m/z
(relative intensity) 312 (MH+, 100). Anal. (C19H21NO3‚HCl) C, H,
N.
1
afforded a product that had an H NMR spectrum identical to the
spectrum for (()-6 and that could be recrystallized from isopropanol
(79% yield): mp 183-195° (dec). Low-resolution ESIMS: m/z
(relative intensity) 270 (MH+, 100). [R]D +165.3° (isopropanol).
Anal. (C16H18ClNO4) C, H, N.
(6aS,12bR)-(-)-2,3-Dihydroxy-6a,7,8,12b-tetrahydro-6H-
chromeno[3,4-c]isoquinoline Hydrochloride ((-)-6). A procedure
identical to the one used above for (()-6 but starting with (+)-23
(6aS,13bR)-(-)-6-[(2R)-2-Methoxy-2-phenylacetyl]-5,6a,7,-
13b-tetrahydro-6H-[1,3]methylenedioxy[6,7]chromeno[3,4-c]i-
soquinoline ((-)-27). The procedure used by Knoerzer28 was
followed. R-(-)-R-Methoxyphenylacetic acid (714 mg, 4.30 mmol)
was placed into a round-bottom flask containing 12 mL of SOCl2.
This solution was stirred for 1 h at room temperature. The solvent
was then removed by rotary evaporation, followed by repeated
addition of benzene and subsequent evaporation to azeotropically
remove residual SOCl2 to provide R-(-)-O-methylmandeloyl
chloride. This acyl chloride was dissolved in 5 mL of dry CH2Cl2
and added to a round-bottom flask containing 930 mg (3.31 mmol)
of amine 23 in a stirring suspension of 20 mL of CH2Cl2 and 10
mL 0.5 M NaOH. This heterogeneous mixture was vigorously
stirred for 6 h, the layers were then separated, the aqueous layer
was extracted with CH2Cl2 (30 mL), and the combined organic layer
was washed with water (2 × 30 mL) and brine (50 mL). The organic
layer was then dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was separated by silica column
chromatography using 2:1 hexanes-EtOAc as the eluent to obtain
616 mg (43%) of a faster moving component, Rf ) 0.32, identified
as the desired amide: mp 170 °C. [R]D -125.0° (CH2Cl2). 1H NMR
(CDCl3): δ 7.32 (d, 1H, ArH), 7.30-7.24 (m, 5, ArH), 7.20 (t,
2H, ArH), 6.98 (t, 1H, ArH), 6.93 (s, 1H, ArH), 6.51 (s, 1H, ArH),
6.22 (d, 1H, ArH), 5.93 (d, 2H, OCH2O), 5.13 (s, 1H, OCHAr),
5.08 (m, 1H, ArOCH), 4.88 (d, 1H, ArCH2N, J ) 14.7 Hz), 4.17
(m, 2H, Ar2CH, ArCH2N), 3.75 (m, 2H, CHN, ArOCH), 3.60 (s,
3H, OCH3). Low-resolution CIMS: m/z (relative intensity) 430
(MH+, 100). Anal. (C26H23NO5) C, H, N.
(6aR,13bS)-(+)-6-[(2R)-2-Methoxy-2-phenylacetyl]-5,6a,7,-
13b-tetrahydro-6H-[1,3]methylenedioxy[6,7]chromeno[3,4-c]i-
soquinoline ((+)-28). Fractions eluting later from the chromato-
graphic separation detailed above yielded 661 mg (46%) of a slower
moving component (Rf ) 0.20): mp 186 °C. [R]D +197.2° (CH2-
Cl2). 1H NMR (CDCl3): δ 7.45 (d, 1H, ArH), 7.35-7.33 (m, 5H,
ArH), 7.24 (t, 1H, ArH), 7.07 (t, 1H, ArH), 6.93 (s, 1H, ArH),
6.62 (d, 1H, ArH), 6.51 (s, 1H, ArH), 5.93 (d, 2H, OCH2O), 5.13
(m, 1H, OCH), 5.02 (s, 1H, ArCHO), 4.85 (d, 1H, ArCHN, J )
14.2 Hz), 4.15 (m, 1H, ArCHAr), 4.05 (d, 1H, ArCHN, J ) 14.2
Hz), 3.76-3.71 (m, 2H, CHN, OCH), 3.42 (s, 3H, OCH3). Low-
resolution CIMS: m/z (relative intensity) 430 (MH+, 100). Anal.
(C26H23NO5) C, H, N.
1
afforded a product that had an H NMR spectrum identical to the
spectrum for (()-6 and that could be recrystallized from isopropanol
(81% yield): mp 183-195° (dec). Low-resolution ESIMS: m/z
(relative intensity) 270 (MH+, 100). [R]D -165.1° (isopropanol).
Anal. (C16H18ClNO4) C, H, N.
Pharmacology. Materials. [3H]Spiperone (95 Ci/mmol) and [3H]-
SCH-23390 (81 Ci/mmol) were purchased from Amersham Bio-
sciences (Piscataway, NJ). [3H]Cyclic AMP (30Ci/mmol) was
purchased from Perkin-Elmer (Boston, MA). Quinpirole, dopamine,
chlorpromazine, SCH-23390, butaclamol, isobutylmethylxanthine,
forskolin, and most other reagents were purchased from Sigma-
Aldrich Chemical Co. (St. Louis, MO). Most cell culture reagents,
including growth media and antibiotics, were purchased from Gibco
Invitrogen Corporation (Carlsbad, CA).
Cell Lines. HEK cells stably expressing rat D2L and human D4.4
receptors were constructed as described previously.30 HEK D1
CreLuc cells were created by a two-step process. Briefly, HEK293
cells were cotransfected with the pBabe Puro and pGL-CreLuc
vectors. Puromycin-resistant clones that expressed the functional
cAMP response element-linked luciferase reporter gene were
selected. Next, HEK CreLuc cells were stably transfected with
pcDNA3.1(+)-D1. Clones were assayed for dopamine D1 receptor
function by measuring cAMP accumulation and luciferase activity.
Cell Culture. All cells were maintained in DMEM with 5% fetal
clone serum, 5% bovine calf serum, 0.05 µg/mL penicillin, 50 µg/
mL streptomycin, and 2 µg/mL puromycin (D2L and D4.4) or 300
µg of G418 and 2 µg/mL puromycin (D1 CRE-Luc). Cells were
grown at 37 °C in a humidified incubator with 5% CO2.
Cyclic AMP Accumulation Assay. Assays were performed on
confluent monolayers of cells in 48-well plates. All drugs were
diluted in Earle’s balanced salt solution (EBSS) assay buffer (EBSS
containing 2% bovine calf serum, 0.025% ascorbic acid, and 15
mM HEPES, pH 7.4) and added on ice. Cyclic AMP stimulation
assays were performed in HEK D1 CRE-Luc cells by incubating
ligands with D1 receptors for 15 min at 37 °C. Forskolin (5 µM)
was added to stimulate cAMP production for inhibition assays
performed in HEK D2L and HEK D4.4 cells. All assays were
performed in the presence of 500 µM isobutylmethylxanthine
(IBMX) and terminated with 3% trichloroacetic acid.
Cyclic AMP Binding Assay. cAMP accumulation assays were
quantified using a previously described protocol.31 Briefly, cellular
lysate was added in duplicate to cAMP binding buffer (100 mM
Tris-HCl, pH 7.4, 100 mM NaCl, 5 mM EDTA) in assay tubes
containing [3H]cyclic-AMP (1 nM final concentration) and bovine
adrenal gland cAMP binding protein (100-150 µg in 500 µL of
buffer). These were incubated on ice at 4 °C for 2-3 h and
terminated by harvesting with ice cold wash buffer (10 mM Tris,
0.9% NaCl) using a 96-well Packard Filtermate cell harvester. After
the samples were dried, 30 µL of Packard Microscint O was added
to each well. Radioactivity was counted using a Packard Topcount
scintillation counter. Standard curves ranging from 0.01 to 300 pmol
of cAMP were used to determine the concentration of cAMP in
each sample.
(6aS,12bR)-(-)-2,3-Methylenedioxy-6a,7,8,12b-tetrahydro-
6H-chromeno[3,4-c]isoquinoline ((-)-23). The (-)-27 diastere-
omeric amide (615 mg, 1.433 mmol) was dissolved in 50 mL of
dry THF and stirred at 0 °C. A 1 M solution of LiEt3BH (9 mL, 9
mmol) was added through a syringe, and the solution was stirred
for 12 h at 0 °C. The reaction mixture was then poured into 15 mL
of ice-cooled 2 M HCl, and the aqueous layer was washed with
ether (2 × 15 mL) and then basified with NH4OH. The free amine
was extracted from this aqueous suspension with CH2Cl2 (3 × 15
mL). The crude product was purified by column chromatography
over silica gel, eluting with 1:1 hexanes-EtOAc to provide 374
mg (93%) of the chiral amine: mp 163 °C. 1H NMR: identical to
the data of 23, above. [R]D -35.3° (CH2Cl2). Low-resolution
CIMS: m/z (relative intensity) 282 (MH+, 100). Anal. (C17H15-
NO3) C, H, N.
(6aR,12bS)-(+)-2,3-Methylenedioxy-6a,7,8,12b-tetrahydro-
6H-chromeno[3,4-c]isoquinoline ((+)-23). The (+)-28 diastere-
omeric amide was treated identically to (-)-27 to yield the chiral
amine (94% yield): mp 163 °C. 1H NMR spectrum identical
to that for (-)-23. [R]D +35.3° (CH2Cl2). Low-resolution CIMS:
m/z (relative intensity) 282 (MH+, 100). Anal. (C17H15NO3) C, H,
N.
Competition Binding Experiments. Porcine striatal tissue was
obtained fresh from the Purdue Butcher Block and prepared as
previously described.32 Briefly, striatal tissue was homogenized
using a potter-type homogenizer, suspended in homogenization
buffer (20 mM Hepes, 0.32 M sucrose, pH 7.4), and spun at 1000g
for 10 min at 4 °C. The pellet (P1) was discarded, and the
supernatant was centrifuged at 30000g for 10 min at 4 °C. The

6856 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23
CueVa et al.
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resulting pellet (P2) was resuspended in 50 mM Tris buffer (pH
7.4) by briefly using a Kinematica homogenizer and then centri-
fuged at 30000g for 30 min at 4 °C. This pellet was resuspended
again in 50 mM Tris buffer, dispensed into 1 mL aliquots, and
centrifuged for 10 min at 13000g and 4 °C. A BCA protein assay
was used to determine the final protein concentration of the pellets.
Supernatant was aspirated and pellets were frozen at -80 °C
until use.
Radioligand binding assays were performed as previously
described, with only minor modifications.33 Pellets were resus-
pended (1 mL/mg) in receptor binding buffer (50 mM Hepes, 4
mM MgCl2, pH 7.4), and 75 µg of protein was used per assay tube.
Receptor isotherms were performed with [3H]SCH-23390 and [3H]-
spiperone to determine Bmax and Kd for D1-like and D2-like receptor
sites (760 fmol/mg and 0.44 nM for [3H]SCH-23390; 250 fmol/
mg and 0.075 nM for [3H]spiperone). All D2-like receptor binding
assays were performed in the presence of 50 nM ketanserin to mask
5-HT2A sites. Nonspecific binding was defined with 5 µM butaclam-
ol. Drug dilutions for competitive binding experiments were made
in receptor binding buffer and added to assay tubes containing 75
µg of protein and either 1 nM [3H]SCH-23390 or 0.15 nM [3H]-
spiperone. All binding experiments were incubated for 30 min at
37 °C and were terminated and counted in a fashion similar to the
cAMP binding assays.
Data Analysis. GraphPad Prism software was used to generate
dose-response, receptor isotherm, and competition binding curves
and to perform statistical analyses (GraphPad Software, San Diego,
CA). Data from cAMP inhibition assays performed in HEK D2L
and HEK D4.4 cells were normalized to percent maximum forskolin-
stimulated cAMP accumulations defined by GraphPad Prism, and
Hill slopes were fixed to generate EC50 values. Maximum inhibition
values for D2 and D4.4 functional experiments were fixed to that of
quinpirole in order to estimate EC50 values of low potency
compounds. Data from D1 cAMP stimulation assays were normal-
ized to 10 µM dopamine. For the figures shown in this paper, data
from competition binding experiments were normalized to percent
of specific binding, and the bottoms of agonist curves were fixed
to zero. Ki values were calculated using the Cheng-Prusoff
equation.
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Acknowledgment. This work was supported by NIH Grants
MH42705 (D.E.N.) and MH60397 from NIMH (V.J.W.) and
by the NIMH PDSP program. The work was conducted in a
facility constructed with support from Research Facilities
Improvement Program Grant No. C06-14499 from the National
Center for Research Resources of the National Institutes of
Health. The authors also acknowledge helpful discussions with
Lisa Bonner.
Supporting Information Available: X-ray crystallographic data
and elemental analysis results. This material is available free of
charge via the Internet at http://pubs.acs.org.
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