10-Substituted 11-oxygenated (R)-aporphines: Synthesis, pharmacology, and modeling of 5-HT(1A) receptor interactions

Article abstract of DOI:10.1021/jm960188q

Derivatives of the selective serotonin 5-HT(1A) receptor agonist (R)- 11-hydroxy-10-methylaporphine (2) having various substituents in the C10- position or at the nitrogen have been synthesized from natural morphine or 6- O-acetylcodeine, respectively. Th

Full text of DOI:10.1021/jm960188q

J . Med. Chem. 1996, 39, 3491-3502
3491
10-Su bstitu ted 11-Oxygen a ted (R)-Ap or p h in es: Syn th esis, P h a r m a cology, a n d
Mod elin g of 5-HT1A Recep tor In ter a ction s
Martin H. Hedberg,† J ohanna M. J ansen,† Gunnar Nordvall,‡ Stephan Hjorth,§ Lena Unelius,‡ and
Anette M. J ohansson*,†
Organic Pharmaceutical Chemistry, Uppsala University, Uppsala Biomedical Centre, Box 574, S-751 23 Uppsala, Sweden,
Preclinical R&D, Astra Arcus AB, S-151 85 So¨derta¨lje, Sweden, and Department of Pharmacology, University of Go¨teborg,
Medicinaregatan 7, S-413 90 Go¨teborg, Sweden
Received March 8, 1996X
Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylapor-
phine (2) having various substituents in the C10-position or at the nitrogen have been
synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents
were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were
evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All
compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition,
changes in steric bulk and/or electronic properties of the C10-substituent as compared to a
C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger
N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected
compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for
their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as
agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-
N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested.
Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group)
appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A
receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to
rationalize the observed affinity data. The binding site model suggests the presence of a “methyl
pocket” in the 5-HT1A receptor binding site. The C11-methoxy-substituted aporphines appear
to have a different binding mode compared to 2, implying a different accessibility of these
compounds to the “methyl pocket”.
In tr od u ction
tivity, we have now synthesized and tested a series of
derivatives of 2 having various substituents in the C10-
position or at the nitrogen. The C10-substituents were
introduced by use of efficient palladium-catalyzed Stille
and Suzuki cross-coupling reactions3 of triflates 52b,c,4
and 8.2b,c The noraporphines were synthesized from
6-O-acetylcodeine (16)5 using a combination of the
previously reported sequence for the synthesis of 22b,c
and N-demethylation/N-alkylation reactions.
The compounds were pharmacologically evaluated in
vitro for their affinities to 5-HT1A, D1, and D2A receptors.
Selected aporphines having high affinities to 5-HT1A
receptors were also evaluated in biochemical and be-
havioral assays in vivo. The difference in 5-HT1A
receptor binding profiles were rationalized by modeling
of ligand-receptor interactions using a homology-based
receptor model of the 5-HT1A receptor binding site.
Various analogues of the nonselective dopamine (DA)
agonist (R)-apomorphine (1) have been prepared previ-
ously in order to explore structure-activity relation-
ships (SAR) of this class of conformationally rigid DA
analogues at D1 and D2 receptors.1 One of these
compounds, (R)-11-hydroxy-10-methylaporphine (2, HY-
MAP),2 lacks dopaminergic effects but displays potent
and selective serotonin 5-HT1A receptor agonist
properties.2a,c In addition, the nonselective D1 receptor
antagonist (R)-11-hydroxyaporphine (4)1c is a weak
partial 5-HT1A receptor agonist having affinity also to
D2A receptors.2c
Ch em istr y
Syn th esis. The novel aporphines 9-14 were pre-
pared following the synthetic strategy described recently
for compounds 2-4 and 7.2b,c,6 The methods used are
shown in Scheme 1.
The cross-coupling reactions of triflate 82b,c with
stannanes were performed following the recently re-
ported procedure for sterically hindered, electron-rich
aryl triflates.3a This procedure appeared to be superior
to earlier protocols.3b,c Compound 9 was prepared from
8 by cross-coupling with tributyl(2-furyl)stannane. At-
tempts to use (2-furyl)boronic acid7 as the transmeta-
lating agent in a Suzuki reaction3d,e were unsuccessful.
In order to study the importance of the C10- and
N-substituents in 2 for serotonergic potency and selec-
* Correspondence and reprints: Dr. Anette M. J ohansson. Phone:
+46-18-174336. Fax: +46-18-174024. E-mail: Anette@bmc.uu.se.
† Uppsala University.
‡ Astra Arcus AB.
§ University of Go¨teborg.
X Abstract published in Advance ACS Abstracts, August 1, 1996.
S0022-2623(96)00188-4 CCC: $12.00 © 1996 American Chemical Society

3492 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18
Hedberg et al.
Sch em e 1a
a
Reagents: (a) PhB(OH)2, Pd(PPh3)4, LiCl, EtOH, DME, 2 M aqueous Na2CO3, reflux; (b) MeSO3H, N2, 95 °C; (c) i. MeSO3H, N2, ii.
CH2N2, Et2O, CHCl3; (d) tributyl(2-furyl)stannane, (PPh3)2PdCl2, PPh3, LiCl, DMF, 120 °C; (e) i. (PPh3)2PdCl2, LiCl, tributyl(1-
ethoxyvinyl)stannane, PPh3, DMF, 120 °C, ii. 1 M HCl, THF; (f) BBr3, CHCl3, rt; (g) tributylvinylstannane, PPh3, LiCl, (PPh3)2PdCl2,
DMF, 120 °C; (h) H2, 10% Pd(C), THF; (i) 48% HBr, N2, reflux. Tf ) CF3SO2-.
This can be compared with the successful result re-
Sch em e 2a
ported with triflate 54 in a similar Suzuki reaction and
may be due to the increased sterical hindrance in
compound 8.8 Cross-coupling of 8 with tributyl(1-
ethoxyvinyl)stannane followed by acid hydrolysis of the
intermediate vinyl ether gave 10. Attempts to perform
a Heck coupling of 8 with butyl vinyl ether9 were
unsuccessful. The vinyl derivative 12 was obtained by
cross-coupling of tributylvinylstannane with 8. The
C10-ethyl derivative 13 was obtained by hydrogenation
of 12. Cross-coupling of 8 with tetraethylstannane was
not attempted due to the presumed ease of â-hydride
elimination from the postulated intermediate trans-bis-
(triphenylphosphine)ethyl[(R)-11-methoxyaporphin-10-
yl]palladium(II). This would probably give the hydro-
genolysis product (R)-11-methoxyaporphine1c,2 as the
main product, in analogy with results reported by Saa´
et al.3a Demethylation of 10 and 13 gave 11 and 14,
respectively. In an attempt to synthesize 11 from 154
by an acid-catalyzed rearrangement, we isolated the
retro-Friedel-Crafts product 4 (73% yield). Similar
reactions have been reported previously for various
ketones.10 The preparation of 8 from triflate 5 has been
described previously.2c
6-O-Acetylcodeine (16)5 was utilized as starting mate-
rial in the synthetic sequence leading to the norapor-
phine derivatives (Schemes 2 and 3). This approach was
attractive because few successful methods for N-dem-
ethylation of aporphines have been reported in the
literature. Cyanogen bromide,11 chloroformates,12 or
diethyl diazodicarboxylate13 produce ring opening of the
aporphine skeleton, leading to the isolation of (amino-
ethyl)phenanthrene derivatives. Treatment of an apor-
a
phine with hydrogen peroxide, to give the corresponding
N-oxide, followed by reductive N-demethylation with
liquid sulfur dioxide as described by Cava and Srini-
vasan,14 gave a low yield of the desired noraporphine.
The use of electron transfer photooxidation for the
Reagents: (a) i. CH3CHClOCOCl, Cl(CH2)2Cl, reflux, ii.
MeOH, reflux, iii. HCl (aq), MeOH; (b) propanal, NaBH4, EtOH,
H2O, HOAc, NaOAc, 0 °C; (c) BBr3, CH2Cl2, N2, -10 to -2 °C; (d)
PhN(Tf)2, CH2Cl2, Et3N, N2, rt or reflux; (e) MeSO3H, N2, 95 °C;
(f) CH2N2, CHCl3, ether; (g) Me4Sn, PPh3, LiCl, (PPh3)2PdCl2,
DMF, 120 °C; (h) 48% HBr, N2, reflux. Tf ) CF3SO2-.

10-Substituted 11-Oxygenated (R)-Aporphines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18 3493
Sch em e 3a
and a subsequent hydrogenolysis gave 30. Alkylation
of 30 with 2-iodopropane using the conditions described
by Liu et al.24 gave 33, which was O-demethylated to
34. Cross-coupling of 26 with tetramethylstannane
afforded 32, which was rearranged in methanesulfonic
acid to 29. Hydrogenolysis of 29 gave 31, the nor-
analogue of 2. An alternative synthesis of 31 was
performed by demethylation of 30.
Molecu la r Mod elin g. Low-energy conformations of
selected nonprotonated (R)-aporphines were identified
by molecular mechanics MM2(91)25 calculations using
the torsion angle driver procedure as described
previously.2c When studying intermolecular interac-
tions between the ligand and active site residues, the
protonated form of the ligands was used.
A model of the human 5-HT1A receptor, based on a
presumed homology in three-dimensional structure
between bacteriorhodopsin and the G-protein-coupled
receptors,26,27 has been constructed previously.2c This
model was adjusted to correct for the revision of the
amino acid sequence of the 5-HT1A receptor.28 Based
on results from mutation studies and previous modeling
of receptor-ligand interactions,2c,28,29 Asp116, Ser199,
and Phe362 were initially considered as interaction
points in the 5-HT1A receptor model. Allowed conforma-
tions of these Asp and Ser residues were probed in Sybyl
by a systematic search around their side chain torsion
angles. Starting orientations of 2 in the resulting
5-HT1A models were obtained by fitting extended N+-H
and O-lone pair points onto the Asp-O and Ser-O; as a
third fitting point, an extended normal through the
A-ring was used to fit onto the centroid of the Phe
residue. The rms value of the fit was used together with
the common volume of ligand and active site residues
to select complexes for further optimization.
Active site optimization was performed in the pseu-
doreceptor/minireceptor modeling program Yak30 in a
stepwise manner using high-affinity ligands of increas-
ing size: 4, 2, and (R)-11-phenylaporphine (35).31 Prior
to Yak optimization, two spheres were defined around
the ligand(s) of interest by selecting residues that had
atoms within 5 and 7.5 Å of ligand atoms, respectively.
All residues within the 7.5 Å sphere were transferred
to Yak where the residues in the inner 5 Å sphere were
optimized; the additional residues in the outer shell
served to maintain the overall shape of the binding site.
Refinement of the site by optimization of multiple
ligands simultaneously was performed with 3 and 5 Å
spheres, respectively. Yak minimizations were per-
formed on both ligand(s) and residues simultaneously
using the all-atom Yeti force field while keeping the
backbone atoms fixed.32 Translational and rotational
degrees of freedom were considered for the ligand(s),
whereas only torsional degrees of freedom were consid-
ered for the amino acids. Active site complexes result-
ing from Yak optimization of one ligand were used as
the starting point for docking the next high-affinity
ligand by fitting that ligand onto the optimized position
of the first ligand using the protonated nitrogen, the
C11-oxygen (C11 for 35), and the A-ring centroid.
a
Reagents: (a) PhCH2Br, K2CO3, DMF, rt; (b) BBr3, CH2Cl2,
N2, -10 to -2 °C; (c) PhN(Tf)2, CH2Cl2, Et3N, N2, rt or reflux; (d)
MeSO3H, N2, 95 °C; (e) CH2N2, CHCl3, ether; (f) Me4Sn, PPh3, LiCl,
(PPh3)2PdCl2, DMF, 120 °C; (g) H2, 10% Pd(C), HOAc; (h) 2-io-
dopropane, diisopropylethylamine, K2CO3, CH3CN, 70 °C; (i) 48%
HBr, N2, reflux. Tf ) CF3SO2-.
N-demethylation of an aporphine as described by San-
tamaria et al.15 would probably offer a possibility to
perform N-demethylation at the aporphine stage instead
but requires special equipment. In contrast, N-dem-
ethylation of 16 using 1-chloroethyl chloroformate, as
reported by Olofson et al.,12a gives an excellent yield of
the corresponding norcodeine derivative under compa-
rably mild conditions and with a simplified workup
procedure in comparison to other methods.16
N-Demethylation12a of 16 followed by hydrolysis of the
resulting acetate gave 1717 (Scheme 2). Reductive
amination of propanal18 with 17 afforded 18,19 which
was demethylated using a modified version of the
protocol reported by Rice20 to produce 19.21 Intermedi-
ate 21 was synthesized from 19 using a protocol
described previously.2b,c Cross-coupling of 21 with tet-
ramethylstannane afforded 22, which was demethylated
to give 23, the N-propyl analogue of 2.
N-Alkylation of 17 with benzyl bromide afforded 24,22
which was demethylated to 2523 and further converted
to triflate 26 (Scheme 3). Acid-catalyzed rearrangement
of 26 followed by O-methylation produced 27. Cross-
coupling of 27 with tetramethylstannane afforded 28,
Optimization of 4 in the 5-HT1A site resulted in
interactions of this ligand with Asp116 and Ser168.
Optimization of 2 in this site gave rise to unfavorable
steric interactions between Asp116 and Asn386, as well
as an unsatisfactory fit of the ligand. Manual adjust-

3494 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18
Ta ble 1. Physical Data of Novel (R)-Aporphines
Hedberg et al.
recrystn
solventsa
[R]rt (deg)
D
compd
R1
R2
R3
mp (°C)
yield (%)
(c 1.0, MeOH)
formula
C23H21NO‚HCl
22H21NO2‚H2C2O4‚1/4H2O
7
9
OH
Ph
Me
Me
Me
Me
Me
Me
Me
Pr
Pr
Pr
Bn
Bn
Bn
H
246-250b
133-137
209-213b
247-251b
242-246b
247-249b
227-230b
183-185
226-229b
185-188
134-138b
218-222
206-210b
272-276b
313-315b,d
206-210
198-203
67
79
66
74
71
76
61
71
86
85
84
88
77
92
71
84
94
A
-52.0
-129.7
-179.6
-143.3
-238.5
-201.0
-107.4
-73.0
-189.1
-94.9
-33.0
-128.0
-45.4c
-222.9
-121.2
-202.2
-101.0
OMe
OMe
OH
OMe
OMe
OH
OMe
OMe
OH
OMe
OMe
OH
2-furyl
COMe
COMe
CHdCH2
Et
C
10
11
12
13
14
21
22
23
27
28
29
30
31
33
34
A
A
A
B
A
C
D
C
C20H21NO2‚HCl
C19H19NO2‚HCl
C20H21NO‚HCl
C20H23NO‚HCl
Et
C19H21NO‚HCl‚1/4H2O
OTf
Me
C21H22F3NO4S‚HCl
C21H25NO‚HCl
20H23NO‚HCl
C25H23F3NO4S‚HCl
Me
C
OTf
Me
C
25H25NO‚HCl‚1/4H2O
Me
Me
Me
Me
A
C24H23NO‚HCl‚1/2H2O
C18H19NO‚HCl
OMe
OH
OMe
OH
A and D
A
C
H
2-Pr
2-Pr
C17H17NO‚HCl
C
C
21H25NO‚HCl
Me
E and F
20H23NO‚HCl‚1/2H2O
a
b
A: MeOH/ether. B: 2-PrOH/ether. C: MeCN/ether. D: MeCN. E: CHCl3/ether. F: EtOH/EtOAc. Decomposition. c (c 0.50, MeOH).
d
Green at 280-282 °C.
ment of the torsion angles of Asp116, followed by
optimization in Yak, relieved the unfavorable interac-
tions and resulted in a better fit of the ligand, again
interacting with both Asp116 and Ser168. An ad-
ditional manual adjustment was made to accomplish a
hydrogen bond between Ser199 and Ser168. The sub-
sequent optimization of 35 in the active site resulted in
a reorientation of this ligand placing the large C11-
substituent in a hydrophobic pocket while maintaining
the interaction of the protonated amine with Asp116.
In a final step, both 2 and 35 were optimized together
to yield the general model used for docking the current
series of aporphines (Figure 1).
In our previous modeling study of ligand-5-HT1A
receptor interactions,2c Ser199 hydrogen bonds to the
oxygen-containing moiety at C11 in the aporphines. In
the model of the active site optimized to interact with
2, Ser199 could indeed be rotated to hydrogen bond to
the ligand. This interaction was however not compat-
ible with the general model that also includes the
nonoxygenated compound 35. In addition, the hydrogen
bond between Ser199 and Ser168 was lost when includ-
ing 35 in the general model.
Possible binding modes of the different conformations
of selected compounds in the 5-HT1A receptor were
examined by fitting the protonated N, (C11)O, and
A-ring centroid of these structures onto 2 as docked in
the active site. The 5 and 3 Å spheres were defined
around the whole set of fitted ligands, and the resulting
site was used to optimize the orientation of the indi-
vidual ligands, together with the torsional degrees of
freedom of the amino acids in the 3 Å sphere in Yak.
F igu r e 1. Schematic representation of the interaction be-
tween 2 and the 5-HT1A receptor binding site showing only
the helices involved in receptor-ligand interactions. A rein-
forced ionic bond between Asp116 and the protonated nitrogen,
a hydrogen bond between Ser168 and the C11-hydroxyl group,
and an edge-to-face interaction between Phe362 and the A-ring
of 2 represent key interactions. Also indicated is the presence
of the “methyl pocket”.
P h a r m a cology
Recep tor Bin d in g Stu d ies. The compounds were
examined in vitro for their ability to displace [3H]-8-
OH-DPAT, [3H]SCH23390, and [3H]raclopride binding
to rat hippocampal 5-HT1A, rat striatal D1, and cloned
human D2A receptors, respectively (Table 2). The recep-
tor binding assays were performed essentially as de-
scribed previously.2c All compounds tested have a
decreased affinity to 5-HT1A receptors as compared to
2. The noraporphine 31 has the highest selectivity for
5-HT1A sites of the compounds tested. All novel com-

10-Substituted 11-Oxygenated (R)-Aporphines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18 3495
Ta ble 2. Affinities of Selected Aporphines for Rat Brain
5-HT1A and D1 Receptor Recognition Sites Labeled by
[3H]-8-OH-DPAT and [3H]SCH23390, Respectively, and at
Cloned Human D2A Receptors Expressed in Ltk- Cells and
Labeled by [3H]Raclopride
significant decrease in the DOPA levels in limbic
forebrain and striatum.
Stimulation of postsynaptic 5-HT1A receptors by means
of agonists like (R)-8-hydroxy-2-(dipropylamino)tetralin
[(R)-8-OH-DPAT] results in a clear-cut motor behavioral
syndrome, the “5-HT syndrome”, in rats. Flattened
body posture, forepaw treading, and hindlimb abduction
are the most prominent features of this syndrome.35c,39
The ability of compounds 2, 23, and 31 to stimulate
putative postsynaptic 5-HT1A receptors was thus as-
sessed by rating the occurrence and intensity of these
behavioral components in reserpinized rats (Table 4).
Immediately after this scoring session the rats were
injected with NSD1015 and subsequently used for
determination of brain 5-HT and catecholamine syn-
thesis rates as described above. The known 5-HT1A
receptor agonist 2 was inactive at the dose tested (0.33
µmol/kg). However, 2 has been shown to induce a clear
5-HT syndrome at a higher dose (13 µmol/kg).40 Com-
pound 31 (3.5 µmol/kg) induced a clear-cut 5-HT syn-
drome, whereas 23 (30 µmol/kg) was inactive in this
assay. These in vivo pharmacological data indicate that
2 and 31 are full agonists at 5-HT1A receptors. The
relatively high affinity of 23 to 5-HT1A receptors (Table
2) coupled with its inability to reduce 5-HT synthesis
or induce the behavioral 5-HT syndrome might suggest
that 23 possesses weak partial agonist or antagonist
properties at these sites. However, further work is
needed to support this suggestion.
Ki (nM)a
[3H]-8-OH-DPAT
(5-HT1A
[3H]SCH23390
(D1)b
[3H]raclopride
b
compd
)
(D2A)
1
2
3
4
7
296 ( 15c
0.45 ( 0.13c
7.5 ( 1.8
9.6 ( 3.1c
1090 ( 270
1621 ( 319
995 ( 7
150 ( 39
1720 ( 300
108 ( 13
17.5 ( 0.2
9.2 ( 0.3
3300 ( 465
10.8 ( 0.2
12.3 ( 1.5
1380 (36
772 ( 60
12.6 (0.6
3.2 ( 0.2
640 (120
241 (14
236d
41.9 ( 4.7c
1070 ( 54c
248 ( 32
58.5 ( 9.5c
>1000
382 ( 35c
393 ( 15
20.4 ( 1.0c
9400 ( 270
>2000
8
9
1040 ( 62
582 ( 62
2980 ( 180
2760 ( 260
1750 ( 550
411 ( 38
2050 (n ) 1)
403 ( 106
238 ( 32
249 ( 46
>5000
14 000 ( 3200
4820 ( 900
4620 ( 470
1440 ( 92
1030 ( 30
782 ( 42
>2000
10
11
12
13
14
21
22
23
28
29
30
31
33
34
>2000
>2000
>5000
>5000
>1000
>5000
4710 ( 3500
>10 000
23 800 ( 2800
>5000
>1000
>1000
>10 000
a
The Ki values are means ( standard errors of n ) 2-3
b
experiments. None of the compounds tested produced a clear
biphasic binding profile at the D1 and/or D2A receptor. Therefore
the results have been interpreted in terms of a one-site model.
d
c From ref 2c. From ref 33.
Discu ssion
pounds display lower D1 and D2A receptor affinities as
compared to the previously investigated 133 and 4.1c,2c
The N-propylnoraporphine 23 displays increased affin-
ity to D2A receptors compared to its N-methylated
analogue 2.
On the basis of the in vitro receptor binding data, it
may be concluded that a change of the steric bulk and/
or the electronic properties of the C10-substituent in 2
reduces the affinity of the compounds to 5-HT1A recep-
tors. For example, the C10-ethyl derivative 14 dis-
played a 20-fold decrease in affinity to 5-HT1A receptors
as compared to 2. The effects of various C10-substitu-
ents on the 5-HT1A receptor binding affinity support the
tentative presence of a lipophilic “methyl pocket” in the
5-HT1A receptor binding site as was previously sug-
gested by modeling studies of ligand-5-HT1A receptor
interactions.2c In the minireceptor model, the C10-
methyl group of 2 is surrounded by Gly164, Phe165,
Ser199, Gly202, Ala203, and Ile206 (Figure 1). Al-
though an additional effect of the C10-methyl substitu-
ent on the conformational behavior of the C11-hydroxy
group cannot be ruled out,2a the reduced affinity of the
C10-ethyl-substituted 14 may be explained by a com-
bination of steric repulsion and the fact that the
conformation of the ethyl substituent most compatible
with the site has a relative steric energy of 1.2 kcal/
mol. Optimization of C11-hydroxy-, -methoxy-, and
-phenyl-substituted aporphines in the active site showed
a gradual change in binding orientation as described
elsewhere in more detail.31 This change implies a
different position of the C10-substituent in C11-meth-
oxylated vs C11-hydroxylated compounds. Whereas the
C10-methyl-substituent of 2 appears to perfectly fit into
a lipophilic pocket, the same substituent in the C11-
methoxylated compound 3 does not occupy this pocket
quite as well and, therefore, does not enhance binding
affinity. A change of the C10-substituent from methyl
to ethyl has a more dramatic effect on affinity in the
C11-hydroxylated series than in the C11-methoxylated
Bioch em istr y a n d Beh a vior . The rationale for the
in vivo biochemical experimental protocol is based on
the well-established phenomenon of (auto)receptor-
mediated feedback inhibition of presynaptic monoam-
inergic neurons.34 Thus, the synthesis of 5-HT, DA, and
norepinephrine (NA) is inhibited by 5-HT, DA, and
R-adrenoceptor agonists, respectively. The in vivo ef-
fects of single doses of compounds 2, 23, and 31 on
5-hydroxytryptophan (5-HTP)/dihydroxyphenylalanine
(DOPA) accumulation following decarboxylase inhibition
by means of (3-hydroxybenzyl)hydrazine dihydrochlo-
ride (NSD1015, 117 mg/kg sc) were investigated in
limbic forebrain, striatum, and cortex of reserpine-
pretreated rats (Table 3).35 The accumulation of 5-HTP
following decarboxylase inhibition was taken as an
indicator of the 5-HT synthesis rate in all three brain
parts, whereas the accumulation of DOPA was taken
as index of the synthesis rates of DA and NA in DA
receptor-rich parts (limbic forebrain, striatum) and NA-
predominated regions (cortex), respectively.36 Com-
pounds 2 (0.33 µmol/kg) and 31 (3.5 µmol/kg) decreased
the cerebral 5-HTP levels by 30-40% and 50-60%,
respectively. ED50 values were determined for these two
compounds in all three brain regions to be 0.2, 0.3, and
0.3 µmol/kg for 2 and 1.3, 0.8, and 1.5 µmol/kg for 31 in
limbic forebrain, striatum, and cortex, respectively.
Compound 23 produced no effect on 5-HTP levels at the
dose tested (3.0 µmol/kg). These results indicate that
2 and 31 are agonists at synthesis-controlling 5-HT1A
autoreceptors.34c,d,37 Compound 23 produced a small but

3496 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18
Hedberg et al.
Ta ble 3. Effects of Selected (R)-Aporphines on Central 5-HTP and DOPA Accumulation in Reserpine-Pretreated Rats
5-HTP accumulation:a percent of
saline controls, mean ( SEM
DOPA accumulation:b percent of
saline controls, mean ( SEM
dose
compd
(µmol/kg)
n
limbic forebrain
striatum
cortex
limbic forebrain
striatum
cortex
2
23
31
0.33
3.0
3.5
2
4
3
58 ( 2*
104 ( 11
37 ( 4*
70 ( 8*
104 ( 13
47 ( 5*
72 ( 9*
102 ( 15
40 ( 3*
84 ( 8
81 ( 9*
85 ( 6
90 ( 2
100 ( 6
116 ( 13
93 ( 7
72 ( 9*
78 ( 12
a
Shown is the amount of accumulated 5-HTP in percent of saline controls (for 2 and 31, 100% limbic forebrain 235 ( 33 ng/g, striatum
187 ( 11 ng/g, cortex 95 ( 11 ng/g, n ) 4; for 23, 100% limbic forebrain 164 ( 11 ng/g, striatum 158 ( 14 ng/g, cortex 123 ( 15 ng/g, n
) 3), means ( SEM, n ) 2-4. Statistical differences were calculated by one-way ANOVA followed by Fischer’s protected least-significant-
b
difference test (PLSD): * p < 0.05 vs. saline controls. Shown is the amount of accumulated DOPA in percent of saline controls (for 2 and
31, 100% limbic forebrain 765 ( 50 ng/g, striatum 3526 ( 323 ng/g, cortex 103 ( 11 ng/g, n ) 4; for 23, 100% limbic forebrain 674 ( 40
ng/g, striatum 2511 ( 173 ng/g, cortex 100 ( 7 ng/g, n ) 3, means ( SEM, n ) 2-4. Statistical differences were calculated by one-way
ANOVA followed by Fischer’s PLSD: *p < 0.05 vs saline controls.
Ta ble 4. Postsynaptic 5-HT1A Receptor-Mediated Behaviora
the interaction of 2 with a homology-based model for
the D2A receptor.2c
dose
∑ scores
compd
(µmol/kg)
median (range)
n
In summary, these results indicate that some of the
analogues of 2 presented in this study bind with fair
affinity to 5-HT1A receptors and are able to stimulate
5-HT1A receptors in rats. The 10-methyl-11-hydroxy-
N-methyl substitution pattern in 2 seems to be optimal
for a potent interaction between the 5-HT1A receptor and
the aporphines, as was suggested by Cannon et al.42 The
5-HT1A receptor affinities may be rationalized by model-
ing of ligand-receptor interactions using homology-
based model building and minireceptor optimization. A
slightly different orientation of C11-methoxylated vs
C11-hydroxylated aporphines and also the presence of
a methyl pocket accommodating the C10-methyl sub-
stituent of 2 are crucial elements in the interaction site
model.
saline control
0 (0-1)
0 (0-0)
0 (0-0)
3 (1-5)
3
3
3
3
2
23
31
0.33
30
3.5
a
Behavioral scores according to a 4-point intensity-based rating
scale (0 ) absent, 1 ) equivocal, 2 ) clearly present, 3 ) intense).
Rating period 60 s bin, 30 min after drug administration, just
before NSD1015 injection. Rats were pretreated with reserpine
(5 mg/kg, sc) 18-20 h before.
series (compare 2 and 14 to 3 and 13), again indicating
a different position of the C10-substituent (Figure 2).
The low affinity of the C10-acetyl derivative 11 to
5-HT1A receptors may be due to an energetically favored,
resonance-stabilized intramolecular hydrogen bond be-
tween the phenol group and the carbonyl oxygen of this
aporphine41 [IR (CCl4) 1634 cm-1 (CdOstr), indicating
the presence of an intramolecular hydrogen bond42b].
Docking of this conformation into the receptor model
results in unfavorable interactions between the carbonyl
group of 11 and the carbonyl of Gly164 and between
the acetyl-CH3 and the backbone of Gly202 and Ala203.
The methoxy analogue 10 [IR (CCl4) 1681 cm-1 (CdOstr)]
is unable to form this hydrogen bond and displays more
than 10-fold higher affinity (Table 2).
Compounds 28, 29, 33, and 34 displayed particularly
low affinities to 5-HT1A and DA D1/D2A receptors,
probably due to steric repulsions between the binding
sites and the bulky N-benzyl and N-isopropyl groups.
The space available for N-alkyl substituents in the
5-HT1A receptor model is limited due to the presence of
the Phe361 residue.
The data from the pharmacological evaluations in
vitro and in vivo indicate that 2 and 31 are full agonists
at 5-HT1A receptors. Compound 2 has an approximately
7-fold higher affinity for the 5-HT1A receptor in vitro
than 31 but appears less efficiacious in vivo (higher dose
to elicit 5-HT1A appropriate behavior). This apparent
paradox may be explained by the fact that 2 has not
been behaviorally tested over an extended dose range
(only 0.33 and 13 µmol/kg). Thus, the discrepancy may
well be resolved by performing full behavioral dose-
response studies with either agent. None of the novel
compounds showed any pronounced affinity to D1 and
D2A receptors in the assays used. In addition, 23 only
produced a slight decrease in DOPA accumulation in
the dose tested. Introduction of various carbon substit-
uents in the C10-position of the aporphine skeleton
appears to unfavorably influence the interaction with
DA receptors as was previously rationalized by modeling
Exp er im en ta l Section
Ch em istr y. Gen er a l Com m en ts. Melting points (uncor-
rected) were determined in open glass capillaries using an
Electrothermal melting point apparatus. Optical rotation
measurements were obtained on a Perkin-Elmer 241 polarim-
eter. Elemental analyses (C, H, N) were performed at Mik-
rokemi AB, Uppsala, Sweden, and were within (0.4% of the
theoretical values. Infrared (IR) spectra were recorded on a
Perkin-Elmer 298 spectrophotometer. 1H and 13C NMR spec-
tra were recorded on a J EOL J NM-EX270 spectrometer at 270
and 64.8 MHz, respectively, and referenced to internal tet-
ramethylsilane. Assignment of signals from the morphine
derivatives was done in accordance with previously published
material.2c,43 Thin-layer chromatography (TLC) was performed
by using aluminum sheets precoated with either silica gel 60
F254 or aluminum oxide 60 F254 E neutral (0.2 mm, activity
II-III; E. Merck). For preparative TLC, plates precoated with
either silica gel F254 (2.0 mm) or aluminum oxide F254 T (1.5
mm) (E. Merck) were used. Column chromatography was
performed on silica gel 60 (230-400 mesh; E. Merck) or
aluminum oxide 90 (70-230 mesh; E. Merck). The orga-
nostannanes were purchased from Aldrich and used as deliv-
ered. Dimethylformamide (DMF) was distilled from calcium
hydride and stored over 4 Å molecular sieves under nitrogen.
Physicochemical properties of novel aporphines are also given
in Table 1.
(-)-3-Deoxy-3-p h en ylm or p h in e (6). A mixture of 52b,c,4
(200 mg, 0.479 mmol), phenylboronic acid (88 mg, 0.72 mmol),
(PPh3)4Pd (14 mg, 0.012 mmol), and LiCl (41 mg, 0.96 mmol)
was dissolved in 4 mL of 1,2-dimethoxyethane (DME) under
nitrogen. After stirring for 10 min, EtOH (1 mL) and 2 M
aqueous Na2CO3 (0.72 mL) were added. The mixture was
refluxed under nitrogen at 95 °C for 3 h and then diluted with
CHCl3. The organic layer was extracted with 10% aqueous
NaHCO3, dried (K2CO3), filtered, and concentrated. The
brown, oily residue was chromatographed [silica gel; CHCl3/
MeOH (19:1) and (9:1) followed by aluminum oxide; CHCl3/
MeOH (39:1)] to give, after recrystallization from ether/
pentane, 132 mg (80%) of pure 6:2b IR (KBr) 3550 cm-1 1H
;

10-Substituted 11-Oxygenated (R)-Aporphines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18 3497
F igu r e 2. Stereorepresentation of the interaction of 2 (red) and 13 (green) with the 5-HT1A receptor binding site model. The
different orientations of the C11-hydroxylated 2 and the C11-methoxylated 13 are shown.
NMR (CDCl3) δ 1.94 (ddd, 1 H), 2.11 (ddd, 1 H), 2.37 (app dd,
1 H), 2.45 (ddd, 1 H), 2.47 (s, 3 H), 2.63 (ddd, 1 H), 2.71-2.73
(m, 1 H), 3.12 (app d, 1 H), 3.38 (dd, 1 H), 4.18-4.22 (m, 1 H),
4.92 (dd, 1 H), 5.33 (ddd, 1 H), 5.66-5.72 (m, 1 H), 6.72 (app
d, 1 H), 7.23-7.32 (m, 2 H), 7.36-7.45 (m, 1 H), 7.40 (d, 1 H),
7.68-7.72 (m, 2 H); 13C NMR (CDCl3) δ 21.1, 35.9, 40.9, 42.3,
43.1, 46.4, 58.7, 66.5, 90.7, 119.9, 120.6, 127.0, 127.6, 127.9,
128.3, 128.4, 128.5, 129.0, 130.4, 133.5, 134.6, 136.6, 155.9.
Anal. (C23H23NO2) C, H, N.
°C under nitrogen. The volatiles were evaporated, and the
residue was partitioned between ether and water. The ether
layer was concentrated, and the residue was dissolved in a
mixture of THF (30 mL) and 1 M HCl (10 mL) and stirred
until TLC indicated complete hydrolysis of the intermediate
vinyl ether (30 min). The volatiles were evaporated, and the
residue was partitioned between CHCl3 and 10% aqueous
NaHCO3. The organic layer was dried (K2CO3), filtered, and
concentrated to give a residue, which was chromatographed
[aluminum oxide; ether/hexanes (3:2) followed by silica gel;
CHCl3/MeOH (39:1)]. The amine was converted into the
hydrochloride salt, which was recrystallized from MeOH/ether
to give 90 mg of pure 10‚HCl. The mother liquor from the
recrystallization was extracted between CHCl3 and 10% aque-
ous NaHCO3. The organic layer was dried (K2CO3), filtered,
and concentrated, and the residue was chromatographed using
preparative TLC [aluminum oxide; ether/hexanes (3:2)]. The
amine [IR (CCl4) 1681 cm-1] was converted into the hydro-
chloride salt, which was recrystallized from MeOH/ether to
give 86 mg of pure 10‚HCl (a total yield of 66%): IR (KBr)
2380, 1680 cm-1; 1H NMR (CD3OD) δ 2.66 (s, 3 H), 2.96 (dd, 1
H), 3.10-3.25 (m, 1 H), 3.21 (s, 3 H), 3.41-3.67 (m, 3 H), 3.57
(s, 3 H), 3.79-3.89 (m, 1 H), 4.50 (app br d, 1 H), 7.27 (app d,
1 H), 7.30 (app d, 1 H), 7.43 (dd, 1 H), 7.55 (d, 1 H), 8.28 (app
d, 1 H); 13C NMR (CD3OD) δ 26.8, 31.2, 32.9, 42.2, 53.4, 62.4,
62.8, 125.7, 128.0, 128.2, 129.7, 129.8, 130.0, 130.3, 131.2,
132.2, 135.6, 140.4, 158.4, 202.3.
(-)-(R)-10-Acet yl-11-h yd r oxya p or p h in e (11). Com-
pound 11 was prepared using a modified version of the
procedure of McOmie et al.44 A solution of 10 (136 mg, 0.442
mmol) in CHCl3 (5 mL) was added dropwise to a stirred
solution of BBr3 (0.25 mL, 2.6 mmol) in CHCl3 (10 mL) at room
temperature under nitrogen. After stirring for 15 min, the
solution was poured into a stirred two-phase system of CHCl3
and 10% aqueous NaHCO3. The combined organic extracts
were dried (Na2SO4), filtered, and concentrated. The residue
was chromatographed [silica gel; CHCl3 to CHCl3/MeOH (39:
1) gradient], and the amine [IR (CCl4) 1637 cm-1] was
converted into the hydrochloride salt. Recrystallization from
MeOH/ether gave 108 mg (74%) of pure 11‚HCl: IR (KBr)
2500, 1635 cm-1; 1H NMR (CD3OD) δ 2.68 (s, 3 H), 2.95 (dd, 1
H), 3.06-3.22 (m, 1 H), 3.18 (s, 3 H), 3.35-3.57 (m, 3 H), 3.74-
3.88 (m, 1 H), 4.38 (dd, 1 H), 7.01 (app d, 1 H), 7.23 (app d, 1
H), 7.39 (dd, 1 H), 7.89 (d, 1 H), 8.40 (app d, 1 H); 13C NMR
(CD3OD) δ 26.7, 27.1, 33.4, 41.5, 53.5, 62.7, 120.4, 121.0, 123.0,
128.9, 129.0, 129.2, 129.5, 130.6, 132.2, 132.5, 143.2, 161.1,
207.0.
(-)-(R)-11-H yd r oxy-10-p h en yla p or p h in e (7).2b Com-
pound 7 was prepared from 6 following a procedure described
previously.2b A solution of 6 (71 mg, 0.21 mmol) in MeSO3H
(2 mL) was heated under nitrogen at 95 °C for 15 min. The
acidic mixture was added dropwise to a stirred two-phase
system of CHCl3 and 10% aqueous NaHCO3 to pH 9. The
aqueous layer was extracted with CHCl3, dried (Na2SO4),
filtered, and concentrated. The black residue was chromato-
graphed [silica gel; CHCl3/MeOH (9:1) and aluminum oxide;
ether/hexanes (4:1) followed by CHCl3/MeOH (9:1)] followed
by preparative TLC [silica gel; CHCl3/MeOH (9:1)]. The amine
was converted into the hydrochloride salt, which was recrys-
tallized from MeOH/ether to give 50 mg (67%) of pure 7‚HCl:
IR (KBr) 2520, 3360 cm-1; 1H NMR (CD3OD) δ 2.89 (dd, 1 H),
3.08-3.20 (m, 1 H), 3.20 (s, 3 H), 3.33-3.59 (m, 3 H), 3.76-
3.85 (m, 1 H), 4.37 (dd, 1 H), 7.01 (app d, 1 H), 7.14 (app d, 1
H), 7.20 (d, 1 H), 7.34-7.53 (m, 5 H), 7.37 (dd, 1 H), 8.39 (app
d, 1 H); 13C NMR (CD3OD) δ 26.9, 33.2, 41.7, 53.5, 63.6, 121.6,
123.2, 128.5, 128.6, 129.0, 129.2, 129.6, 129.8, 130.5, 130.6,
131.5, 132.3, 133.8, 134.8, 139.6, 152.3.
(-)-(R)-10-(2-F u r yl)-11-m eth oxya p or p h in e (9). A solu-
tion of 82b,c (98 mg, 0.236 mmol), (PPh3)2PdCl2 (20 mg, 0.028
mmol), PPh3 (37 mg, 0.14 mmol), and LiCl (82 mg, 1.9 mmol)
in DMF (2 mL) was stirred at room temperature under
nitrogen. After 5 min, tributyl(2-furyl)stannane (0.17 g, 0.47
mmol) dissolved in 3 mL of DMF and 2 crystals of 2,6-di-tert-
butyl-4-methylphenol were added. After stirring for 20 min
at 120 °C under nitrogen, the mixture was cooled and
partitioned between CH2Cl2 and 10% aqueous NaHCO3. The
organic layer was dried (K2CO3), filtered, and concentrated.
The residue was chromatographed using preparative TLC
[aluminum oxide; ether/hexanes (3:2) followed by silica gel;
CH2Cl2/MeOH (9:1)]. The amine was converted into the
oxalate salt, which, after drying at 0.1 mmHg at 55 °C, gave
80 mg (79%) of pure 9‚oxalate: IR (KBr) 2520, 1720 cm-1; 1H
NMR (CD3OD) δ 2.92 (dd, 1 H), 3.05-3.18 (m, 1 H), 3.15 (s, 3
H), 3.34-3.59 (m, 3 H), 3.49 (s, 3 H), 3.76-3.88 (m, 1 H), 4.41
(dd, 1 H), 6.56 (dd, 1 H), 7.03 (app d, 1 H), 7.20 (app d, 1 H),
7.25 (app d, 1 H), 7.41 (1 H, dd), 7.58 (dd, 1 H), 7.74 (d, 1 H),
8.38 (app d, 1 H); 13C NMR (CD3OD) δ 26.6, 32.7, 41.5, 53.3,
60.1, 63.0, 111.0 , 113.0, 125.8, 126.5, 127.2, 128.0, 129.5, 129.8,
131.2, 132.8, 135.2, 143.1, 151.1, 155.4, 166.6.
(-)-(R)-11-Meth oxy-10-vin yla p or p h in e (12). A solution
of 8 (400 mg, 0.965 mmol), LiCl (336 mmol, 7.91 mmol), PPh3
(152 mg, 0.579 mmol), and (PPh3)2PdCl2 (81 mg, 0.12 mmol)
in DMF (10 mL) was stirred at room temperature under
nitrogen. After 10 min, tributylvinylstannane (612 mg, 1.93
mmol) and 3 crystals of 2,6-di-tert-butyl-4-methylphenol were
added. After stirring for 1 h at 120 °C under nitrogen, the
volatiles were removed in vacuo and the residue was parti-
tioned between ether and water. The organic layer was
extracted with 10% aqueous KF, dried (K2CO3), filtered, and
concentrated. The residue was chromatographed [aluminum
(-)-(R)-10-Acetyl-11-m eth oxya p or p h in e (10). A solu-
tion of 8 (323 mg, 0.779 mmol), LiCl (271 mg, 6.39 mmol), PPh3
(123 mg, 0.467 mmol), and (PPh3)2PdCl2 (66 mg, 0.093 mmol)
in DMF (10 mL) was stirred under nitrogen at room temper-
ature. After 5 min tributyl(1-ethoxyvinyl)stannane (0.53 mL,
1.56 mmol) and 3 crystals of 2,6-di-tert-butyl-4-methylphenol
were added. The reaction mixture was stirred for 2 h at 120

3498 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18
Hedberg et al.
oxide; ether/hexanes (3:2)] to give pure amine. The amine was
converted into the hydrochloride salt, which was recrystallized
from MeOH/ether to give 224 mg (71%) of pure 12‚HCl: IR
reaction mixture was extracted with 10% aqueous NaHCO3.
The organic layer was dried (Na2SO4), filtered, and concen-
trated. The residue was chromatographed [silica gel; CHCl3/
MeOH (39:1-9:1) gradient], and the amine was recrystallized
from absolute EtOH to give 0.96 g (67%) of pure 19: mp 227-
230 °C (lit.21 mp 225-228 °C).
1
(KBr) 2500 cm-1; H NMR (CD3OD) δ 2.87 (dd, 1 H), 3.13-
3.63 (m, 4 H), 3.19 (s, 3 H), 3.50 (s, 3 H), 3.77-3.85 (m, 1 H),
4.44 (dd, 1 H), 5.34 (dd, 1 H), 5.82 (dd, 1 H), 7.10 (dd, 1 H),
7.18 (app d, 1 H), 7.26 (app d, 1 H), 7.42 (dd, 1 H), 7.55 (d, 1
H), 8.37 (app d, 1 H); 13C NMR (CD3OD) δ 26.8, 32.8, 41.8,
53.4, 61.2, 63.3, 115.8, 125.7, 127.3, 127.4, 128.1, 129.4, 129.6,
129.9, 130.9, 132.5, 132.9, 133.3, 135.6, 156.8.
(-)-N-P r op yl-3-O-[(tr iflu or om eth yl)su lfon yl]n or m or -
p h in e (20). The preparation of compound 20 was performed
using a slightly modified version of the procedure reported for
the synthesis of 5.2b,c Thus, a solution of 19 (1.30 g, 4.15 mmol)
and Et3N (1.15 mL, 9.30 mmol) in CH2Cl2 (0.1 L) was stirred
for 10 min at room temperature under nitrogen. K2CO3 (0.61
g, 5.0 mmol) and N-phenyltrifluoromethanesulfonimide (1.78
g, 4.98 mmol) were added, and the resulting slurry was
refluxed for 4.5 h. The crude solution was filtered and
concentrated, to give a residue which was chromatographed
[silica gel; CHCl3/MeOH (39:1)]. The amine was converted into
the hydrochloride salt, which was recrystallized from MeCN
(-)-(R)-10-Eth yl-11-m eth oxya p or p h in e (13). Palladium
on charcoal (10%, 0.10 g) was added to a solution of 12 (113
mg, 0.388 mmol) in THF (20 mL). The resulting slurry was
stirred under H2 (1 atm) at room temperature for 3 h. The
mixture was diluted with CH2Cl2, and the catalyst was filtered
off (Celite). The volatiles were evaporated, and the residue
was chromatographed [silica gel; CHCl3/MeOH (39:1) and
aluminum oxide; ether/hexanes (1:8-1:1), stepwise gradient].
The amine was converted into the hydrochloride salt, which
was recrystallized from 2-PrOH/ether to give 97 mg (76%) of
to give 1.77 g (89%) of pure 20‚HCl: mp 250-253 °C dec; [R]23
D
-52.9° (c 1.0, MeOH); IR (film) 3554, 2508, 1221, 1140 cm-1
.
1
pure 13‚HCl: IR (KBr) 2500 cm-1; H NMR (CD3OD) δ 1.25
Anal. (C20H23F3NO5S‚HCl) C, H, N.
(t, 3 H), 2.59-2.85 (m, 2 H), 2.86 (dd, 1 H), 3.10-3.23 (m, 1
H), 3.19 (s, 3 H), 3.36-3.64 (m, 3 H), 3.50 (s, 3 H), 3.79-3.86
(m, 1 H), 4.42 (app br d, 1 H), 7.12 (app d, 1 H), 7.20 (d, 1 H),
7.25 (app d, 1 H), 7.41 (dd, 1 H), 8.35 (app d, 1 H); 13C NMR
(CD3OD) δ 15.7, 24.1, 27.1, 32.7, 42.3, 53.6, 61.0, 63.6, 125.4,
126.9, 127.9, 129.2, 129.6, 129.9, 130.7, 130.9, 133.4, 133.5,
139.3, 157.4.
A small sample of the hydrochloride (0.12 g, 0.25 mmol) was
converted to the amine by extraction between CHCl3 and 10%
aqueous NaHCO3. The organic layer was dried (K2CO3),
filtered, and concentrated to give 0.11 g (99%) of pure 20: IR
(film) 3564, 1219, 1140 cm-1; 1H NMR (CDCl3) δ 0.94 (t, 3 H),
1.53 (sext, 2 H), 1.88 (ddd, 1 H), 2.09 (ddd, 1 H), 2.31 (ddd, 1
H), 2.33 (dd, 1 H), 2.41-2.51 (m, 2 H), 2.61-2.76 (m, 2 H),
2.53-2.89 (br s, 1 H), 3.03 (app d, 1 H), 3.46 (dd, 1 H), 4.13-
4.25 (m, 1 H), 5.01 (dd, 1 H), 5.28 (ddd, 1 H), 5.63-5.75 (m, 1
H), 6.62 (app d, 1 H), 6.88 (d, 1 H); 13C NMR (CDCl3) δ 11.9,
20.9, 21.9, 35.4, 40.6, 44.0, 44.4, 56.5, 57.0, 66.6, 93.7, 118.7
(q), 120.2, 121.0, 128.6, 130.6, 133.5, 134.0, 136.0, 149.5.
(-)-(R)-11-Meth oxy-N-p r op yl-10-[[(tr iflu or om eth ylsu l-
fon yl]oxy]n or a p or p h in e (21). Compound 21 was synthe-
sized from 20 (1.38 g, 3.10 mmol) using a procedure described
previously.2b,c The reaction time was 2 h for the acid-catalyzed
rearrangement and 4 h for the etherification of the intermedi-
ate phenol with CH2N2. Crude 21 was purified by column
chromatography [aluminum oxide; ether/hexanes (1:1) and
silica gel; ether/hexanes (1:1)]. The amine was converted into
the hydrochloride salt, which was recrystallized from MeCN/
ether to give, after pump-drying at 0.5 mmHg and 60 °C, 1.05
g (71%) of pure 21‚HCl: 1H NMR (CD3OD) δ 1.11 (t, 3 H),
1.83-2.03 (m, 2 H), 2.95 (dd, 1 H), 3.14-3.34 (m, 2 H), 3.40-
3.69 (m, 4 H), 3.69 (s, 3 H), 3.94-3.99 (m, 1 H), 4.56 (app br
d, 1 H), 7.30-7.34 (m, 3 H), 7.43 (dd, 1 H), 8.24 (app d, 1 H);
13C NMR (CD3OD) δ 11.3, 18.4, 26.9, 32.3, 50.3, 56.9, 61.3,
61.7, 120.2 (q), 122.9, 126.3, 128.0, 129.6, 130.0, 130.3, 130.4,
131.7, 136.7, 144.6, 151.2.
(-)-(R )-11-Me t h o x y -10-m e t h y l-N -p r o p y ln o r a p o r -
p h in e (22). Compound 22 was synthesized from 21 (422 mg,
0.956 mmol) using a procedure described previously.2c The
reaction time was 6 h. Crude 22 was purified by column
chromatography [aluminum oxide; ether/hexanes (1:1)]. The
amine was converted into the hydrochloride salt, which was
recrystallized from MeCN; yield, 254 mg (86%) of pure 22‚-
HCl: 1H NMR (CD3OD) δ 1.11 (t, 3 H), 1.79-2.04 (m, 2 H),
2.32 (s, 3 H), 2.88 (dd, 1 H), 3.08-3.65 (m, 6 H), 3.52 (s, 3 H),
3.87-3.98 (m, 1 H), 4.46 (dd, 1 H), 7.09 (app d, 1 H), 7.17 (d,
1 H), 7.24 (app d, 1 H), 7.40 (dd, 1 H), 8.34 (app d, 1 H); 13C
NMR (CD3OD) δ 12.2, 17.2, 19.1, 27.9, 33.3, 51.0, 57.7, 61.0,
62.7, 126.0, 127.6, 128.6, 129.8, 130.5, 130.7, 132.0, 132.8,
133.8, 134.1, 134.5, 158.4.
(-)-(R)-10-Eth yl-11-h yd r oxya p or p h in e (14). A slurry of
13‚HCl (101 mg, 0.306 mmol) in 5 mL of freshly distilled 48%
aqueous HBr was refluxed at 120 °C under nitrogen for 3 h.
EtOH (99%) was added, and the volatiles were evaporated.
The residue was partitioned between CHCl3 and 10% aqueous
NaHCO3. The organic layer was dried (Na2SO4), filtered, and
concentrated to give a residue which was column chromato-
graphed [silica gel; CHCl3 to CHCl3/MeOH (39:1) gradient]
followed by preparative TLC [silica gel; CH2Cl2/methanol (9:
1)]. The amine was converted into the hydrochloride salt,
which was recrystallized from MeOH/ether to give 59 mg (61%)
of pure 14‚HCl: IR (KBr) 3260, 2460 cm-1; 1H NMR (CD3OD)
δ 1.22 (t, 3 H), 2.69 (q, 2 H), 2.82 (dd, 1 H), 3.10-3.25 (m, 1
H), 3.19 (s, 3 H), 3.29-3.59 (m, 3 H), 3.78-3.83 (m, 1 H), 4.33
(app br d, 1 H), 6.87 (app d, 1 H), 7.07 (d, 1 H), 7.18 (app d, 1
H), 7.37 (dd, 1 H), 8.35 (app d, 1 H); 13C NMR (CD3OD) δ 14.8,
24.4, 26.8, 33.1, 41.9, 53.4, 63.7, 121.3, 122.5, 128.2, 128.7,
129.2, 129.5, 129.9, 130.4, 132.8, 133.1, 134.1, 153.1.
(-)-N-P r op yln or cod ein e (18).19 Compound 18 was syn-
thesized from 17 using the conditions for reductive amination
reported by Schellenberg.18 A solution of 17 (3.72 g, 0.0130
mol), NaOAc (2.14 g, 0.0260 mol), and HOAc (11 mL) was
added to a stirred mixture of H2O (120 mL) and absolute EtOH
(40 mL) at 0 °C. Propanal (4.7 mL, 0.065 mol) was added
followed by 20 mg portions of NaBH4 (2.45 g, 0.065 mol). After
20 min another portion of propanal (4.7 mL, 0.065 mol) and
20 mg portions of NaBH4 (2.45 g, 0.065 mol) were added. The
mixture was stirred for 30 min, and 5 M aqueous NaOH was
added to pH 12. The basic mixture was extracted with CH2-
Cl2, and the organic layer was dried (K2CO3), filtered, and
concentrated. The residue was chromatographed [silica gel;
CHCl3/MeOH (19:1)]. The pure amine was converted into the
oxalate salt, which was recrystallized from MeOH/ether to give
4.71 g of pure 18‚oxalate: mp 187-189 °C; [R]21 -97.3° (c
D
1.0, MeOH). Anal. (C20H25NO3‚H2C2O4‚1/4H2O) C, H, N.
The residue from the recrystallization was converted to the
amine by extraction between CH2Cl2 and saturated aqueous
Na2CO3. The organic layer was dried (K2CO3), filtered, and
concentrated. The residue was chromatographed [silica gel;
CHCl3/MeOH (39:1)] to give 0.11 g (total yield 88%) of pure
18. Data from 1H NMR for 18 in CDCl3 were identical with
previously reported data.19
(-)-(R )-11-H y d r o x y -10-m e t h y l-N -p r o p y ln o r a p o r -
p h in e (23). Compound 23 was synthesized from 22‚HCl (192
mg, 0.558 mmol) using the procedure described for the
preparation of 14‚HCl. The reaction time was 4 h. Crude 23
was purified by column chromatography [silica gel; CHCl3/
MeOH (39:1)] and preparative TLC [silica gel; CHCl3/MeOH
(19:1)]. The amine was converted into the hydrochloride salt,
which was recrystallized from MeCN/ether to give 156 mg
(85%) of pure 23‚HCl: 1H NMR (CD3OD) δ 1.09 (t, 3 H), 1.73-
2.01 (m, 2 H), 2.26 (s, 3 H), 2.83 (dd, 1 H), 2.98-3.62 (m, 6 H),
3.82-3.89 (m, 1 H), 4.30 (app br d, 1 H), 6.80 (app d, 1 H),
7.00 (d, 1 H), 7.13 (app d, 1 H), 7.33 (dd, 1 H), 8.32 (app d, 1
(-)-N-P r op yln or m or p h in e (19).21 Compound 19 was
prepared from 18 using a modified version of the procedure of
Rice.20 A solution of 18 (1.49 g, 4.55 mmol) in CH2Cl2 (0.20 L)
was stirred at -30 °C under nitrogen. BBr3 (15 mL of a 0.91
M solution in CH2Cl2) was added dropwise. The temperature
was allowed to reach -2 °C, and after stirring for 2 h, the

10-Substituted 11-Oxygenated (R)-Aporphines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18 3499
H); 13C NMR (CD3OD) δ 11.4, 17.0, 18.5, 26.9, 33.0, 50.2, 56.7,
62.3, 121.0, 122.2, 126.7, 128.2, 128.7, 129.1, 129.7, 130.7,
131.5, 133.1, 134.2, 153.7.
(-)-(R )-N -B e n zy l-11-m e t h o x y -10-m e t h y ln o r a p o r -
p h in e (28). Compound 28 was prepared from 27 (3.92 g, 7.99
mmol) using a procedure described previously.2c The reaction
time was 6 h. Crude 28 was purified by column chromatog-
raphy [alumina; ether/hexanes (1:7-1:4-1:1) gradient]. The
amine was converted into the hydrochloride salt to give 2.74
g (88%) of pure 28‚HCl: 1H NMR (CD3OD) δ 2.32 (s, 3 H),
2.96-3.15 (m, 2 H), 3.22-3.52 (m, 2 H), 3.50 (s, 3 H), 3.60-
3.87 (m, 2 H), 4.36-4.56 (m, 2 H), 5.06 (app br d, 1 H), 7.13
(app d, 1 H), 7.16-7.23 (m, 2 H), 7.37 (dd, 1 H), 7.46-7.75 (m,
5 H), 8.34 (app d, 1 H); 13C NMR (CD3OD) δ 16.4, 27.1, 32.8,
49.5, 59.0, 60.2, 62.4, 125.2, 126.9, 127.9, 129.0, 129.7, 129.9,
130.2, 130.5, 131.1, 131.4, 132.1, 132.8, 133.2, 133.4, 133.7,
157.7.
(-)-(R )-N -B e n zy l-11-h y d r o x y -10-m e t h y ln o r a p o r -
p h in e (29). Compound 29 was synthesized from 32 (0.33 g,
0.92 mmol) using the procedure described for the synthesis of
8. The amount of MeSO3H was 2 mL, and the reaction time
was 1 h. Crude 29 was purified by column chromatography
[silica gel; CHCl3 to CHCl3/MeOH (39:1) gradient]. The amine
was converted into the hydrochloride salt, which was recrys-
tallized from MeOH/ether to give 0.27 g (77%) of pure 29‚-
HCl: 1H NMR (CD3OD, 50 °C) δ 2.30 (s, 3 H), 2.89-3.44 (m,
4 H), 3.57-3.86 (m, 2 H), 4.31-4.49 (m, 2 H), 5.04 (d, 1 H),
6.90 (app d, 1 H), 7.08 (d, 1 H), 7.14 (app d, 1 H), 7.36 (dd, 1
H), 7.44-7.70 (m, 5 H), 8.36 (app d, 1 H); 13C NMR (CD3OD,
50 °C) δ 16.9, 27.0, 33.4, 49.9, 59.2, 62.9, 121.1, 122.4, 127.1,
128.2, 128.9, 129.2, 129.7, 130.2, 130.7, 131.57, 131.64, 132.8,
133.0, 134.3, 153.8.
(-)-N-Ben zyln or cod ein e (24).22 A mixture of 17 (18.66
g, 65.4 mmol) and K2CO3 (36.15 g, 0.262 mol) in DMF (350
mL) was stirred under nitrogen for 5 min at room temperature.
Benzyl bromide (8.16 mL, 68.7 mmol) was added, and the
resulting slurry was stirred at room temperature for 2.5 h.
The reaction mixture was filtered, and the volatiles were
concentrated. The residue was partitioned between ether and
H2O. The ether layer was dried (K2CO3), filtered, and con-
centrated to give the amine. The amine was converted into
the hydrochloride salt to give 25.04 g (92.9%) of pure 24‚HCl:
mp 171-175 °C; [R]21D -117.6° (c 1.0, MeOH). Anal. (C24H25
NO3‚HCl) C, H, N.
-
A small sample of the hydrochloride 24‚HCl (0.20 g, 0.49
mmol) was extracted between CHCl3 and 10% aqueous NaH-
CO3. The organic layer was dried (K2CO3), filtered, and
concentrated to give 0.18 g (99%) of pure 24: 1H NMR (CDCl3)
δ 1.85 (ddd, 1 H), 2.06 (ddd, 1 H), 2.31 (app dd, 1 H), 2.46
(ddd, 1 H), 2.63 (ddd, 1 H), 2.68-2.74 (m, 1 H), 3.08 (app br s,
1 H), 3.09 (app d, 1 H), 3.38 (dd, 1 H), 3.64-3.77 (m, 2 H),
3.81 (s, 3 H), 4.08-4.25 (m, 1 H), 4.89 (dd, 1 H), 5.24 (ddd, 1
H), 5.60-5.74 (m, 1 H), 6.58 (app d, 1 H), 6.67 (d, 1 H), 7.21-
7.44 (m, 5 H); 13C NMR (CDCl3) δ 21.3, 35.8, 40.8, 43.4, 44.5,
56.1, 56.2, 59.2, 66.4, 91.4, 112.6, 119.4, 126.9, 127.2, 128.2,
128.5, 128.6, 131.2, 133.1, 138.9, 142.0, 146.2.
(-)-N-Ben zyln or m or p h in e (25).23 Compound 25 was
prepared from 24 (10.37 g, 0.0252 mol) using the protocol for
the synthesis of 19. The reaction temperature was -10 °C,
and the reaction time was 1 h and 15 min. Crude 25 was
purified by column chromatography [silica gel; CHCl3 to
CHCl3/MeOH (19:1) gradient]. The free amine was recrystal-
lized from absolute EtOH to give 6.34 g (70%) of pure 25: mp
(-)-(R)-11-Met h oxy-10-m et h yln or a p or p h in e (30).
A
mixture of 28‚HCl (1.27 g, 7.99 mmol) and Pd(C) (10%, 0.24
g) in HOAc (20 mL) was stirred at room temperature under
H2 (1 atm) for 7 h. The mixture was diluted with CHCl3/MeOH
(4:1) and filtered through Celite. Crude 30‚HCl was purified
by recrystallization from MeCN followed by MeOH/ether. The
crystals were dried at 0.1 mmHg and 150 °C to give 0.90 g
(92%) of pure 30‚HCl: 1H NMR (CD3OD) δ 2.32 (s, 3 H), 2.89
(dd, 1 H), 3.06-3.18 (m, 2 H), 3.25-3.36 (m, 1 H), 3.36-3.52
(m, 1 H), 3.51 (s, 3 H), 3.71-3.80 (m, 1 H), 4.45 (dd, 1 H), 7.03
(app d, 1 H), 7.16 (d, 1 H), 7.24 (app d, 1 H), 7.40 (dd, 1 H),
8.37 (app d, 1 H); 13C NMR (CD3OD) δ 16.4, 26.3, 34.6, 42.5,
54.3, 60.1, 125.1, 127.0, 127.8, 129.3, 129.76, 129.85, 131.3,
132.1, 133.1, 133.6, 157.9.
227-229 °C (lit.23 mp 230-231 °C); [R]21 -132.6° (c 0.50,
D
MeOH) (lit.23 [R]23 -130°, no concentration given).
D
(-)-N-Ben zyl-3-O-[(t r iflu or om et h ylsu lfon yl]n or m or -
p h in e (26). Compound 26 was synthesized from 25 (5.21 g,
0.014 mol) using the procedure described for the preparation
of 5.2b,c The reaction time was 3.5 h. Crude 26 was treated
with HCl in ether, and the hydrochloride salt formed was
partitioned between CHCl3 and 10% aqueous NaHCO3. The
organic layer was dried (Na2SO4), filtered, and concentrated
to give the amine. Recrystallization of the amine from ether
yielded 6.00 g of pure 26. The mother liquor was concentrated,
and the residue was chromatographed [aluminum oxide;
CHCl3]. Recrystallization from ether afforded 0.32 g (a total
yield of 89%) of pure 26: mp 166-168 °C; [R]21D -80.8° (c 0.50,
(-)-(R)-11-Hydr oxy-10-m eth yln or apor ph in e (31). Meth -
od A. Compound 31 was prepared from 29‚HCl (0.15 g, 0.40
mmol) using the procedure for the preparation of 30‚HCl. The
reaction time was 10 h. Crude 31‚HCl was recrystallized twice
from MeOH/ether to give 82 mg (71%) of pure 31‚HCl: 1H
NMR (CD3OD) δ 2.27 (s, 3 H), 2.87 (dd, 1 H), 3.01-3.14 (m, 2
H), 3.21-3.44 (m, 2 H), 3.64-3.80 (m, 1 H), 4.37 (dd, 1 H),
6.78 (app d, 1 H), 7.03 (d, 1 H), 7.16 (app d, 1 H), 7.35 (dd, 1
H), 8.36 (app d, 1 H); 13C NMR (CD3OD) δ 17.0, 26.3, 34.9,
42.4, 54.4, 120.9, 122.4, 126.7, 128.4, 128.7, 129.1, 129.6, 130.7,
131.4, 133.0, 133.9, 153.9.
Meth od B. Compound 31 was synthesized from 30‚HCl
(155 mg, 0.514 mmol) using the procedure described for the
preparation of 14‚HCl. The reaction time was 6 h. Crude 31
was converted into the hydrochloride salt, which was recrys-
tallized from MeOH/ether, to give 142 mg (96%) of pure 31‚-
HCl.
(-)-N-Ben zyl-3-deoxy-3-m eth yln or m or ph in e (32). Com-
pound 32 was synthesized from 26 (0.58 g, 1.2 mmol) using
the procedure reported for the synthesis of 22. The reaction
time was 3 h. Crude 32 was purified by column chromatog-
raphy [silica gel; CHCl3/MeOH (39:1) and aluminum oxide;
ether to CHCl3 followed by silica; hexane/EtOAc/acetone (1:9:
3)] to give 0.34 g (80%) of pure 32: 1H NMR (CDCl3) δ 1.82
(ddd, 1 H), 2.05 (ddd, 1 H), 2.18 (s, 3 H), 2.30 (app dd, 1 H),
2.45 (ddd, 1 H), 2.62 (ddd, 1 H), 2.67-2.73 (m, 1 H), 2.85 (app
br d, 1 H), 3.09 (app d, 1 H), 3.36 (dd, 1 H), 3.62-3.78 (m, 2
H), 4.05-4.24 (m, 1 H), 4.83 (dd, 1 H), 5.23 (ddd, 1 H), 5.57-
5.70 (m, 1 H), 6.55 (app d, 1 H), 6.82 (d, 1 H), 7.18-7.46 (m,
5 H); 13C NMR (CDCl3) δ 14.6, 21.9, 35.9, 41.0, 43.0, 44.6, 56.3,
59.4, 66.4, 90.4, 116.1, 119.0, 127.0, 128.3, 128.6, 128.7, 129.1,
129.7, 132.6, 133.1, 139.0, 156.9.
1
MeOH); H NMR (CDCl3) δ 1.87 (ddd, 1 H), 2.11 (ddd, 1 H),
2.33 (app dd, 1 H), 2.41 (ddd, 1 H), 2.66 (ddd, 1 H), 2.69-2.76
(m, 1 H), 2.91 (app br d, 1 H), 3.12 (app d, 1 H), 3.42 (dd, 1 H),
3.63-3.77 (m, 2 H), 4.10-4.27 (m, 1 H), 5.02 (dd, 1 H), 5.22
(ddd, 1 H), 5.61-5.73 (m, 1 H), 6.65 (app d, 1 H), 6.90 (d, 1 H),
7.18-7.43 (m, 5 H); 13C NMR (CDCl3) δ 22.0, 35.4, 40.6, 44.0,
44.3, 56.0, 59.3, 66.6, 93.8, 118.7 (q), 120.3, 121.0, 127.2, 128.4,
128.6, 128.7, 130.6, 133.5, 134.1, 135.9, 138.7, 149.6. Anal.
(C24H22F3NO5S) C, H, N.
(-)-(R)-N-Ben zyl-11-m et h oxy-10-[[(t r iflu or om et h yl)-
su lfon yl]oxy]n or a p or p h in e (27). Compound 27 was syn-
thesized from 26 (17.63 g, 35.7 mmol) using the procedure for
the synthesis of 21. The amount of MeSO3H was 45 mL, and
the reaction time was 2 h for the acid-catalyzed rearrange-
ment. The subsequent reaction with CH2N2 was run over-
night. Crude 27 was purified by column chromatography
[aluminum oxide; ether/hexanes (1:1) followed by ether/hex-
anes (1:7-1:4-1:1) gradient]. The amine was converted into
the hydrochloride salt, to give 15.9 g (84%) of pure 27‚HCl:
1H NMR (CD3OD) δ 3.00-3.18 (m, 2 H), 3.20-3.44 (m, 2 H),
3.69 (s, 3 H), 3.72-3.94 (m, 2 H), 4.42 (br d, 1 H), 4.58 (app br
d, 1 H), 5.10 (br d, 1 H), 7.28 (app d, 1 H), 7.34 (app d, 1 H),
7.39 (app d, 1 H), 7.42 (dd, 1 H), 7.49-7.57 (m, 3 H), 7.60-
7.70 (m, 2 H), 8.24 (app d, 1 H); 13C NMR (CD3OD) δ 27.0,
32.9, 49.4, 59.0, 61.7, 61.9, 120.2 (q), 122.9, 126.2, 127.9, 129.7,
129.9, 130.3, 130.5, 131.1, 131.2, 131.7, 132.0, 132.5, 137.0,
144.6, 151.2.

3500 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18
Hedberg et al.
A small sample of 32 was converted into the hydrochloride
salt, which was recrystallized from MeCN/ether to give pure
32‚HCl: mp 190-193 °C; [R]23D -143.4° (c 0.50, MeOH). Anal.
(C24H25NO2‚HCl‚3/4H2O) C, H, N.
resulting sites were filtered to retain those that were compat-
ible with the distance between the ligand -OH and -N+-H
functional groups. The ligand N+-H was therefore extended
to a distance of 2.6 Å, and both O-lone pairs of the ligand were
extended to 2.75 Å. The distance between these extended
points in 2 was 7.96/7.83 Å. When using Ser199, the minimum
distance between Asp-O and Ser-O was 8.84 Å, and the 10 sites
with the smallest distance between Asp-O and Ser-O were
used. Visual inspection revealed that Ser168 came closer to
Asp116, and a systematic search using this Ser residue yielded
a minimum distance in allowed sites of 7.79 Å. From this
Asp116/Ser168 search, also the 10 sites with the smallest
distance between Asp-O and Ser-O were considered. In the
selected sites, the ligand was fitted to the Asp, Ser, and Phe,
and the rms and the common volume were recorded. The
extended points defined above (N+-H and O-lone pairs) were
used to fit onto the Asp-O and Ser-O. For the third fitting
point a normal was defined through the A-ring, extending 6
Å toward the Phe residue. The end point of this normal was
fitted onto the centroid of the phenyl ring of the Phe residue.
The weight of this last fitting point was 1/10th of the weight
of the other two points.
Min ir ecep tor m od elin g. Active site optimization was
performed in Yak version 3.9 (SIAT Biographics Laboratory,
Missionsstrasse 60, CH-4055 Basel, Switzerland). Atomic
charges of ligands transferred to Yak were obtained from a
single-point MNDO calculation (MOPAC version 5.0, imple-
mented in Sybyl 6.0.3). The necessary free energies of binding
and of ligand solvation were obtained from the Ki values and
the program ESOLV (supplied with Yak and based on an
algorithm developed by Still et al.45 ), respectively. Minimiza-
tions started with 25 steps of the steepest-descent minimizer
followed by 25 steps of the conjugate gradient minimizer.
When convergence was not achieved after these 50 steps, a
new 50-step minimization was performed.
P h a r m a cology. Recep tor Bin d in g Assa ys. The 5-HT1A
receptor binding assay was performed essentially as described
previously.2c The modifications compared with the assay in
ref 2c were as follows: (a) the composition of the Tris-HCl
buffer used for the incubation mixtures (50 mM containing
2.0 mM CaCl2, 1.0 mM MgCl2, 1.0 mM MnCl2, 5.7 mM ascorbic
acid, pH 7.4), (b) nonspecific binding measured by the addition
of 100 µM 5-HT‚HCl to the reaction mixture, and (c) the time
for the incubation at 37 °C as 45 min. The DA D1 and D2A
receptor binding assays were performed as previously reported,2c
by measuring the ability of the compounds to displace [3H]-
SCH23390 from rat striatal tissue and [3H]raclopride from
cloned human D2A receptors expressed in mouse fibroblast
(Ltk-) cells, respectively.
Bioch em istr y. The 5-HT and catecholamine synthesis
rates were estimated by measuring the accumulation of
5-hydroxytryptophan (5-HTP) and 3,4-dihydroxy phenylala-
nine (DOPA), respectively, after pretreatment with the aro-
matic L-amino acid decarboxylase inhibitor NSD1015 (117 mg/
kq).36 Male Sprague-Dawley rats (B&K Universal, Sollentuna,
Sweden), weighing 250-300 g, were used. Reserpine pre-
treatment (5 mg/kg, sc) was given 18-20 h before the start of
the experiments. The compounds to be tested were dissolved
in saline immediately before use, occasionally with the addition
of a few drops of glacial HOAc to obtain complete dissolution.
Reserpine (Ciba, Basel, Switzerland) was dissolved in a few
drops of glacial HOAc and made up to volume with 5.5%
aqueous glucose (w/v). All compounds, including reserpine and
NSD1015 (Sigma, St. Louis, MO), were subcutaneously in-
jected in the neck region in a volume of 5 mL/kg. The
biochemical experiments, including brain dissections and
HPLC determinations (electrochemical detection) of tissue
contents of DOPA and 5-HTP, were carried out essentially
according to methods detailed elsewhere.35a,b Empirically, the
maximum decrease of cerebral 5-HTP values obtained with a
direct-acting 5-HT1A receptor agonist, like 8-OH-DPAT, is
about 50% from control values under conditions equivalent to
those used in the present experiments.35c
(-)-(R)-N-Isop r op yl-11-m et h oxy-10-m et h yln or a p or -
p h in e (33). Compound 33 was prepared from 30 according
to a method previously described by Liu et al.24 A mixture of
30 (0.32 g, 1.2 mmol), K2CO3 (0.18 g, 1.3 mmol), and diisopro-
pylethylamine (0.22 mL, 1.3 mmol) in MeCN (1.2 mL) was
stirred at room temperature. After 20 min 2-iodopropane (0.13
mL, 1.3 mmol) was added. The flask was sealed, and the
reaction mixture was stirred at 70 °C for 67 h. The crude
mixture was partitioned between CH2Cl2 and H2O, and the
organic layer was dried (K2CO3), filtered, and concentrated.
The residue was chromatographed [silica gel; CHCl3/MeOH
(39:1) and aluminum oxide; ether/hexanes (1:8)]. The amine
was converted into the hydrochloride salt, which was recrys-
tallized from MeCN/ether to give 0.35 g (84%) of pure 33‚-
HCl: 1H NMR (CD3OD) δ 1.34 (d, 3 H), 1.56 (d, 3 H), 2.31 (s,
3 H), 2.91 (dd, 1 H), 3.12-3.24 (m, 1 H), 3.25-3.52 (m, 3 H),
3.51 (s, 3 H), 3.79-3.89 (m, 1 H), 4.30 (sept, 1 H), 4.59 (dd, 1
H), 7.08 (app d, 1 H), 7.16 (d, 1 H), 7.23 (app d, 1 H), 7.38 (dd,
1 H), 8.34 (app d, 1 H); 13C NMR (CD3OD) δ 14.3, 16.4, 18.8,
27.3, 32.3, 43.5, 54.6, 59.9, 60.2, 125.3, 126.9, 127.8, 129.1,
129.6, 130.4, 131.6, 132.0, 133.1, 133.56, 133.60, 157.6.
(-)-(R)-11-H yd r oxy-N-isop r op yl-10-m e t h yln or a p or -
p h in e (34). Compound 34 was synthesized from 33‚HCl (156
mg, 0.454 mmol) using the procedure described for the
preparation of 14‚HCl. The reaction time was 4 h. Crude 34
was purified by column chromatography [silica gel; CHCl3/
MeOH (39:1) and toluene/MeCN (2:1)]. The amine was
converted into the hydrochloride salt, which was recrystallized
from CHCl3/ether and then EtOH/EtOAc. The crystalline
powder was dried at 0.5 mmHg and 60 °C to give 0.14 g (94%)
of pure 34‚HCl: 1H NMR (CD3OD) δ 1.34 (d, 3 H), 1.54 (d, 3
H), 2.27 (s, 3 H), 2.84 (dd, 1 H), 3.08-3.45 (m, 4 H), 3.72-
3.87 (m, 1 H), 4.28 (sept, 1 H), 4.48 (dd, 1 H), 6.83 (app d, 1
H), 7.03 (d, 1 H), 7.17 (app d, 1 H), 7.35 (dd, 1 H), 8.34 (app d,
1 H); 13C NMR (CD3OD) δ 14.2, 17.1, 18.7, 27.3, 32.7, 43.5,
54.5, 60.2, 121.1, 122.2, 126.7, 128.2, 128.7, 129.1, 130.2, 131.1,
131.5, 133.0, 134.4, 153.6.
Com p u ta tion a l Meth od s. MacMimic version 2.1 (InStar
Software, IDEON Research Park, S-233 70 Lund, Sweden) was
used as graphical interface for MM2(91).25 Torsion angle
drivers on aromatic and N-alkyl substituents were performed
from 0° to 360° with a 10° increment and full energy minimi-
zation except for the dihedral angles used as driving angle(s).
The resulting local minima were built and subjected to
unrestricted energy minimization. Conformational prefer-
ences of compounds 12 and 13 were examined by driving
simultaneously around C11-O (90° increments) and C10-
C(ethyl/vinyl) (30° increments). The most stable conformation
of the aporphine skeleton was used. It has a pseudoequatorial
N-alkyl substituent and adopts a half-chair conformation of
the tetrahydropyridine ring with P-helicity. Conformations
with P-helicity and a pseudoaxial N-substituent, M-helicity
and a pseudoequatorial N-substituent, and M-helicity with a
pseudoaxial N-substituent have relative steric energies of 0.8,
3.1, and 3.6 kcal/mol, respectively (compound 2). Compounds
with a C11-OH substituent were modeled with C10-C11-
O-H in an eclipsed orientation as selected previously for
hydrogen bonding to active site residues.2c
Recep tor Mod elin g. The adjusted 5-HT1A model28 was
further minimized in Sybyl 6.0.3 (Tripos Associates Inc., 1699
S. Hanley Rd., Suite 303, St. Louis, MO) using the following
parameters: AMBER force field (Kollman_all_atoms, Kollman
charges) with conjugate gradient minimizer, a distance di-
electric constant of 4, nonbonded cut-off 9.0. All other param-
eters were Sybyl default.
Active Site Defin ition . Amino acids having atoms within
a 10 Å sphere around the centroid of the CR atoms of Asp116,
Ser199, and Phe362 were considered in the initial active site
definition. A systematic search around ø(1) and ø(2) of the
Asp residue and around ø(1) of the Ser residue was performed
in Sybyl to probe allowed orientations of these functional
groups (resolution 15°, default VDW cut-off values). The
Beh a vior . The occurrence and intensity of flattened body
posture, forepaw treading, and hindlimb abduction were scored
for 60 s 30 min after test compound administration, using an

10-Substituted 11-Oxygenated (R)-Aporphines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18 3501
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intensity-based rating scale, where 0 ) absent, 1 ) equivocal,
2 ) definite, and 3 ) intense.46 The maximum score for the
total set of behavioral items was 9. For reference, a subcu-
taneous dose of 0.1 µmol/kg (R)-8-OH-DPAT, which causes
near maximal postsynaptic 5-HT1A receptor activation, yields
summed scores of 8-9 under similar conditions.46
Ack n ow led gm en t. Professor Uli Hacksell is ac-
knowledged for helpful discussions and constructive
criticism of the manuscript. Skillful technical as-
sistance by Anne-Marie Eriksson and Gun Torell-
Svantesson in the binding assays and by Gerd Leonsson
in the biochemical studies is gratefully acknowledged.
Financial support was obtained from the Swedish
National Board for Industrial and Technical Develop-
ment (NUTEK), Astra Arcus AB, and the Swedish
Medical (No. 7486) Science Research Council.
Su p p or tin g In for m a tion Ava ila ble: Assigned 1H NMR
data (7 pages). Ordering information is given on any current
masthead page.
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