Atropisomeric derivatives of 2′,6′-disubstituted (R)-11-phenylaporphine: Selective serotonin 5-HT7 receptor antagonists [2]

Full text of DOI:10.1021/jm0108505

J . Med. Chem. 2001, 44, 1337-1340
1337
Atr op isom er ic Der iva tives of
2′,6′-Disu bstitu ted
(R)-11-P h en yla p or p h in e: Selective
Ser oton in 5-HT7 Recep tor An ta gon ists
Tero Linnanen,†,§ Magnus Brisander,‡ Lena Unelius,|
Susanne Rosqvist,| Gunnar Nordvall,|
Uli Hacksell, and Anette M. J ohansson*,†,#
Organic Pharmaceutical Chemistry, Uppsala University,
Uppsala Biomedical Centre, Box 574,
SE-751 23 Uppsala, Sweden, Department of Medicinal
Chemistry, Institute of Pharmacy, University of Tromsø,
N-9037 Tromsø, Norway, Local Discovery, Research Area
CNS & Pain Control, AstraZeneca R&D So¨derta¨lje,
SE-151 85 So¨derta¨lje, Sweden, ACADIA Pharmaceuticals,
3911 Sorrento Valley Boulevard,
and (6aR,aR)-14 display pharmacological stereoselec-
tivity. This is one of the few instances in which stereo-
isomers with axial chirality have been demonstrated to
interact in a stereoselective fashion with G-protein-
coupled receptors.7
Ch em istr y. The key intermediate for the synthesis
of the atropisomeric aporphine derivatives, ditriflate (R)-
11, was prepared from the known triflate (R)-83 using
San Diego, California 92121-1402, and
ACADIA Pharmaceuticals, Fabriksparken 58,
DK-2600 Glostrup, Denmark
Received February 12, 2001
In tr od u ction . The most well-known aporphine de-
rivative, (R)-apomorphine [(R)-1], is a prototypic dopa-
minergic agonist.1 In contrast, (R)-aporphine [(R)-2]
itself is less potent as a dopamine (DA) receptor agonist
and displays predominantly serotonergic activity.2 Re-
cently, we described that introduction of a C11-phenyl
substituent in (R)-2, producing (R)-3, increases the
affinity for serotonin 5-HT1A receptors more than 40-
fold, thus leading to a potent 5-HT1A receptor ligand.3
On expanded profiling of (R)-3, we observed that it also
is a relatively potent 5-HT7 receptor4 ligand (Table 1).
the three-step sequence shown in Scheme 1. A Suzuki
coupling reaction8 of (R)-8 and 2,6-dimethoxyphenylbo-
ronic acid gave (R)-9. Demethylation of (R)-9 gave
resorcinol (R)-10, which was treated with N-phenyltri-
fluoromethanesulfonimide to afford (R)-11.
Ditriflate (R)-11 contains diastereotopic triflate groups
(R and â, Scheme 2) and could therefore be utilized for
stereoselective palladium-catalyzed coupling reactions.
A cyano and a methyl substituent were stereoselectively
introduced into the C11-aryl substituent of (R)-11
yielding 90% and 60% de of (6aR,aR)-12 and (6aR,aR)-
13, respectively. In both reactions, 4-10% of the di-
coupled product was also formed. The stereoselectivity
obtained in these reactions is probably due to a pre-
ferred attack by a palladium species on the least
sterically hindered triflate group; triflate R is positioned
away from the aporphine skeleton, while triflate â is
situated above it (for comparison, see the solid-state
conformation of (6aR,aR)- and (6aR,aS)-14 in Figure 1).
Therefore, the conformation of (R)-11 makes triflate R
more accessible for attack by a palladium species. The
pure monotriflates (6aR,aR)-12 and (6aR,aR)-13 were
then converted into the atropisomeric (6aR,aS)- and
(6aR,aR)-14 by palladium-catalyzed methylation and
cyanation, respectively. For these second coupling reac-
tions stronger conditions were required. For example,
introduction of the methyl group in (6aR,aR)-12 re-
quired the more reactive and less sterically hindered
tetramethylstannane instead of tributylmethylstannane
and also a longer reaction time (5 h), compared with
the methylation of (R)-11 (40 min) vide supra. For the
introduction of the cyano group in (6aR,aR)-14 micro-
wave heating was utilized in order to shorten the
No selective 5-HT7 receptor agonists and only a few
putatively selective antagonists, 4-7 (Table 1), have
been reported to date.5 The relatively high affinity of
(R)-3 for 5-HT7 receptors provided an opportunity to
derive potent and selective 5-HT7 receptor ligands by
structural modification of (R)-3. Therefore, we initiated
a synthetic program targeting analogues of (R)-3. Ini-
tially, we focused on variations of the substitution
pattern in the C11-phenyl ring. Herein, we describe the
introduction of substituents in the ortho positions of the
C11-phenyl group. The 2′-CN,6′-Me-substituted ana-
logue (6aR,aS)-14 is the most interesting of the novel
derivatives as it is a potent 5-HT7 receptor antagonist
which exhibits selectivity versus 5-HT1A and D2A recep-
tors. Furthermore, the stable atropisomers6 (6aR,aS)-
* To whom correspondence should be addressed. Tel: +46-18-471-
4336. Fax: +46-18-471-4024. E-mail: anette@bmc.uu.se.
† Uppsala University.
‡ University of Tromsø.
| AstraZeneca R&D So¨derta¨lje.
ACADIA Pharmaceuticals, California.
#
ACADIA Pharmaceuticals, Denmark.
§ Present address: AstraZeneca R&D Lund, SE-221 87 Lund,
Sweden.
10.1021/jm0108505 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/31/2001

1338 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 9
Letters
Sch em e 1a
the proximity in space of the C11-substituent and the
(R)-aporphine skeleton.13
Since the presence of atropisomerism in the com-
pounds described here is due to hindered rotation about
the C11-C1′ bond, the stability14 of two isomers toward
isomerization was determined: although the neutral
(6aR,aS)- and (6aR,aR)-14 were left in H2O (pH 7.4) at
100 °C and the corresponding hydrochloride salts were
dissolved in DMSO and kept at 150 °C for 24 h, no
isomerization was detected by HPLC, demonstrating
that these atropisomers are stable toward isomerization
at temperatures <100 °C for at least 24 h.
a
Reagents: (a) (Ph3P)4Pd, 2,6-(OMe)2PhB(OH)2, K2CO3, DMF;
(b) aq HBr (48%); (c) K2CO3, Et3N, (CF3SO2)2NPh, CH2Cl2.
Biologica l Resu lts a n d Discu ssion . The receptor
affinities of the novel derivatives were evaluated in vitro
at 5-HT7, 5-HT1A, and D2A receptors, essentially as
described before.5d,15 Compounds (R)-1-7 are included
for comparative purposes. The efficacy of the atropiso-
mers, (R)-3, (R)-9, and (R)-10 at 5-HT7 receptors was
studied in CHO cells expressing rat 5-HT7 receptors by
measuring the cAMP formation with and/or without
pretreatment with the endogenous ligand 5-HT. In this
assay, the ability of a compound to fully or partially
reverse the 5-HT-stimulated production of cAMP is a
measurement of antagonism or partial agonism. The
results are presented in Table 1.
Sch em e 2a
The present and previous3 results indicate that a C11-
phenyl group is beneficial for the interaction of (R)-
aporphines with both the 5-HT1A and the 5-HT7 receptor
subtypes. The profile of these derivatives may, however,
be modified by the introduction of symmetrically di-
ortho-substituted C11-phenyl groups such as in (R)-9
[(OMe)2], (R)-10 [(OH)2], and (R)-11 [(OTf)2]. The affini-
ties of these derivatives for D2A, 5-HT1A, and 5-HT7
receptors were decreased with the largest decrease
observed at 5-HT1A receptors. This resulted in com-
pounds with selectivity for the 5-HT7 receptor, the
dimethoxy derivative (R)-9 being the most selective and
also the most potent analogue. It displays a 42- and 156-
fold selectivity for 5-HT7 receptors versus 5-HT1A and
D2A receptors, respectively. Also the introduction of
unsymmetrical diortho-substituted phenyl groups gives
compounds with selectivity for the 5-HT7 receptor. Only
one derivative, (6aR,aS)-15, showed moderate affinity
for 5-HT1A receptors while the other atropisomers were
weaker. The atropisomer (6aR,aS)-14, substituted with
a cyano and a methyl group, is the most potent and
selective atropisomer displaying a Ki value of 3.79 nM
at the 5-HT7 receptors and 37- and 131-fold selectivity
for 5-HT7 versus 5-HT1A and D2A receptors, respectively.
The atropisomeric (6aR,aR)-14 showed the same selec-
tivity for 5-HT7 receptors as (6aR,aS)-14 but was about
5 times less potent. This indicates that both a methyl
and a cyano group are tolerated by the 5-HT7 receptor
although the receptor-ligand interaction appears more
optimal for (6aR,aS)-14 than for (6aR,aR)-14. Atropi-
somers (6aR,aR)- and (6aR,aS)-15, being substituted
with a methyl and a hydroxy group, are less selective
and/or less potent at 5-HT7 receptors as compared to
(6aR,aS)- and (6aR,aR)-14.
a
Reagents: (a) (Ph3P)4Pd, Zn(CN)2, DMF; (b) Pd(OAc)2, dppf,
LiCl, Me4Sn, DMF; (c) Pd(OAc)2, dppf, CoCl3, MeSnBu3, DMF; (d)
separation of isomers; (e) K2CO3, EtOH, H2O; (f) (dba)3Pd2, dppf,
Zn(CN)2, DMF.
reaction time.9 Hydrolysis of the triflate group in
(6aR,aR)-13 gave phenol (6aR,aR)-15. The isomeric
phenol (6aR,aS)-15 was obtained by hydrolysis of a
mixture of (6aR,aS)- and (6aR,aR)-13 (8:2)10 followed
by separation of the isomers.
The solid-state conformation and the relative axial
stereochemistry of each of the atropisomers (6aR,aR)-
and (6aR,aS)-14 were established by single-crystal X-ray
diffraction techniques.11 Thermal ellipsoid plots of the
solid-state conformations are shown in Figure 1. The
torsion angle τ1[C11a-C11-C1′-C2′] is -68.0(6)° and
119.6(5)° in (6aR,aR)- and (6aR,aS)-14, respectively,
giving conclusive evidence for the relative axial config-
uration aR in (6aR,aR)-14 and aS in (6aR,aS)-14. The
relative stereochemistry of the other two atropisomers
was unambiguously assigned by chemical correlation
with the two epimers above.12 The solid-state conforma-
tions of the two epimers are very similar and a best fit
of all C and N atoms gave a root-mean-square (rms)
value of 0.11 Å, the main deviation being observed in
the C11-aryl group. We have previously shown that the
torsion angle between the aromatic A- and C-rings, τ2-
[C11-C11a-C11b-C1], in a calculated idealized (R)-
aporphine skeleton is approximately -24°.5d In (6aR,aR)-
and (6aR,aS)-14, however, τ2 is -28.7(7)° and -30.2(7)°,
respectively. This widened angle probably results from
The high affinity and the preference for 5-HT7 recep-
tors of the novel derivatives are of interest since only a
few antagonists (4-7) with putative selectivity for 5-HT7
have been reported.5 Therefore, we decided to further
characterize the pharmacology of the novel compounds;

Letters
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 9 1339
F igu r e 1. Perspective view (ORTEP) of the solid-state molecules of (6aR,aR)-14‚HCl (left) and (6aR,aS)-14‚HCl (right).
Displacement ellipsoids are represented at the 40% probability level.
Ta ble 1. Effects of the Novel Derivatives on 5-HT7-Mediated Stimulation of cAMP Production in CHO Cells Expressing Rat 5-HT7
Receptors and In Vitro Binding Affinities to 5-HT7, 5-HT1A and D2A Receptors Labeled by [3H]5-HT, [3H]8-OH-DPAT, and
[3H]Raclopride
cAMP production
Ki (nM)a
% inhib of 5-HT-
% stimulation
induced stimulation
[3H]5-HT
(5-HT7)
[3H]8-OH-DPAT
(5-HT1A
[3H]Raclopride
(D2A
b
b
compd
(R)-1
(R)-2
(R)-9
(R)-10
(R)-11
(R)-3
R
R′
concn (nM)
%
concn (nM)
%
)
)
NTc
NT
g
g
NT
i
NT
NT
NT
NT
NT
188 ( 17d
88.0 ( 3.7d
13.0 ( 0.15
36.2 ( 12
296 ( 1e,f
80.0 ( 2.3e,f
554 ( 58
41.9 ( 4.7f
527 ( 296f
2030 ( 345
OMe
OH
OTf
H
OMe
OH
OTf
H
NAh
NA
139 ( 3.2
>1000
708 ( 282
9.78 ( 0.82
>10000
2260 ( 660
NA
NA
NA
NA
NA
1
23 ( 5
30 ( 4
1.8 ( 0.4e,f
778 ( 105
142 ( 24
233 ( 3f
100
10000
1
100
10000
1
100
10000
1
100
10000
1
100
(6aR,aR)-14
(6aR,aS)-14
(6aR,aR)-15
(6aR,aS)-15
Me
CN
Me
OH
CN
Me
OH
Me
i
i
i
i
21 ( 0
20.8 ( 2.1
3.79 ( 0.99
43.1 ( 10
23.0 ( 3.4
2470 ( 220
498 ( 98
42 ( 1
100
33 ( 3
97 ( 3
100
21 ( 5
319 ( 54
3380 ( 300
2500 ( 390
43 ( 5
100
11 ( 1
48.8 ( 8.4
100
10000
72 ( 0
100
4j
31.6
3.31
1.26
18.0 ( 1.2
>7943
3981
105
316
2250 ( 550
5k
6l
170
>10000
7m
355 ( 32
a
The Ki values are means ( standard errors of 2-4 experiments. bAll values are given as percent of the stimulation produced by 100
c
nM 5-HT. The EC50 value for 5-HT is 4.1 ( 0.7 nM. The stimulation produced by 5-HT at 100 nM is 95 ( 5% of that at 1 µM. NT ) not
tested. dFrom ref 5d. Data obtained from competition experiments with rat brain 5-HT1A receptor recognition sites. From ref 3. gThe
e
f
concentrations tested were 10, 100, and 1000 nM. hNA ) no activity. The concentrations tested were 1, 10, 100, 1000, and 10000 nM.
i
jFrom ref 5a. kFrom ref 5b. From ref 5c. mFrom ref 5d.
l
the four atropisomers and (R)-3, (R)-9, and (R)-10 were
tested in a functional assay in order to determine their
efficacy at 5-HT7 receptors. None of the analogues were
able to stimulate the cAMP production in CHO cells
transfected with rat 5-HT7 receptors, and thus, none of
the tested compounds appear to be able to stimulate
5-HT7 receptors. The atropisomers and (R)-3 dose-
dependently inhibited the 5-HT-stimulated cAMP pro-
duction and therefore behaved as 5-HT7 receptor antag-
onists. In agreement with results from the binding
studies, (6aR,aS)-14 was the most potent antagonist.
The pharmacological profiles of these novel derivatives
make them interesting as structural leads for future
medicinal chemistry efforts aiming at highly selective
5-HT7 receptor ligands. Preliminary results of (R)-11-
(2,6-dimethylphenyl)aporphine and (R)-11-(2,6-dicyano-
phenyl)aporphine indicate that also these derivatives
display potency and/or selectivity for 5-HT7 receptors.16
In conclusion, we have prepared stable atropisomeric
biaryl derivatives of (R)-aporphine. These structurally
well-characterized derivatives interact in a stereoselec-
tive fashion with 5-HT7, 5-HT1A, and D2A receptors.

1340 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 9
Letters
Steric Factor in Medicinal Chemistry. Dissymmetric Probes of
Pharmacological Receptors; Plenum Press: New York, 1993; pp
320-321. (d) Ikeura, Y.; Ishichi, Y.; Tanaka, T.; Fujishima, A.;
Murabayashi, M.; Kawada, M.; Ishimaru, T.; Kamo, I.; Doi, T.;
Natsugari, H. Axially Chiral N-Benzyl-N,7-dimethyl-5-phenyl-
1,7-naphthyridine-6-carboxamide Derivatives as Tachykinin NK1
Receptor Antagonists: Determination of the Absolute Stereo-
chemical Requirements. J . Med. Chem. 1998, 41, 4232-4239.
(e) Natsugari, H.; Ikeura, Y.; Kamo, I.; Ishimaru, T.; Ishichi, Y.;
Fujishima, A.; Tanaka, T.; Kasahara, F.; Kawada, M.; Doi, T.
Axially Chiral 1,7-Naphthyridine-6-carboxamide Derivatives as
Orally Active Tachykinin NK1 Receptor Antagonists: Synthesis,
Antagonistic Activity, and Effects on Bladder Functions. J . Med.
Chem. 1999, 42, 3982-3993.
The novel derivatives show a preference for the 5-HT7
receptor subtype and have been characterized as 5-HT7
receptor antagonists. (6aR,aS)-14 is a particularly selec-
tive and potent 5-HT7 receptor antagonist. This will
make it useful as a pharmacological tool in 5-HT
research.
Ack n ow led gm en t. We gratefully acknowledge Dr.
Hans Selander for a generous gift of starting material
and the Department of Lead Discovery, AstraZeneca
R&D So¨derta¨lje, for help with some of the radioligand
binding and efficacy studies. Financial support was
obtained from AstraZeneca R&D So¨derta¨lje, So¨derta¨lje.
(8) (a) Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling
Reactions of Organoboron Compounds. Chem. Rev. 1995, 95,
2457-2483. (b) Suzuki, A. Recent Advances in the Cross-
Coupling Reactions of Organoboron Derivatives with Organic
Electrophiles, 1995-1998. J . Organomet. Chem. 1999, 576, 147-
168.
(9) Microwave heating was carried out with a MicroWell 10 single-
mode microwave cavity from Labwell AB, Uppsala, Sweden.
(10) The 8:2 mixture of (6aR,aS)- and (6aR,aR)-13 was a residue from
the reaction mixture that was purified to give pure (6aR,aR)-13.
(11) The following programs have been used: (a) SHELXS: Sheld-
rick, G. M. Phase annealing in SHELX-90: direct methods for
larger structures. Acta Crystallogr., Sect. A46 1990, 467-473.
(b) SHELXL-93: Sheldrick, G. M. SHELXL-93, Program for the
Refinement of Crystal Structures; University of Go¨ttingen:
Germany, 1993. (c) PLATON-92: Spek, A. L. PLATON-92,
Program for the Analysis of Molecular Geometry; University of
Utrecht: Utrecht, The Netherlands, 1992.
Su p p or tin g In for m a tion Ava ila ble: Tables of crystal
data, structure solution and refinement, atomic coordinates,
and anisotropic displacement parameters for (6aR,aR)- and
(6aR,aS)-14‚HCl; experimental, physical, and spectroscopic
data for (6aR,aR)- and (6aR,aS)-14‚HCl and (6aR,aR)- and
(6aR,aS)-15‚HCl; and experimental details for the pharmaco-
logical evaluation and the single-crystal X-ray diffraction. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Refer en ces
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Aporphine and (+)- and (-)-10-Methylaporphine. J . Med. Chem.
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Aporphines: Synthesis, Pharmacology, and Modeling of D2A and
5-HT1A Receptor Interactions. J . Med. Chem. 1996, 39, 3503-
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(4) Vanhoenacker, P.; Haegeman, G.; Leysen, J . E. 5-HT7 Recep-
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Middlemiss, D. N.; Riley, G. J .; Thomas, D. R.; Upton, N. (R)-
3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]ben-
zenesulfonamide: The First Selective 5-HT7 Receptor Antago-
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H.; Hiranuma, T.; Koyama, M. Tetrahydrobenzindoles: Selective
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(6) Atropisomers are defined as separable isomers resulting from
restricted rotation about a single bond. See: (a) Mislow, K. Intro-
duction to Stereochemistry; W. A. Benjamin: New York, 1965;
p 78. (b) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; J ohn Wiley & Sons: New York, 1994; p 1193.
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Arison, B. H.; Engelhardt, E. L.; Hirschmann, R.; Clineschmidt,
B. V.; Lotti, V. J .; Bunting, P. R.; Ballentine, R. J .; Papp, N. L.;
Flataker, L.; Witoslawski, J . J .; Stone, C. A. Synthesis and
Stereospecific Antipsychotic Activity of (-)-1-Cyclopropylmethyl-
4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
piperidine. J . Med. Chem. 1977, 20, 1013-1019. (b) Randall, W.
C.; Anderson, P. S.; Cresson, E. L.; Hunt, C. A.; Lyon, T. F.;
Rittle, K. E.; Remy, D. C.; Springer, J . P.; Hirshfield, J . M.;
Hoogsteen, K.; Williams, M.; Risley, E. A.; Totaro, J . A. Syn-
thesis, Assignment of Absolute Configuration, and Receptor
Binding Studies Relevant to the Neuroleptic Activities of a Series
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Chem. 1979, 22, 1222-1230. (c) Casy, A. F.; Dewar, G. H. The
(12) The 1H NMR chemical shift of the aromatic methyl group in
epimers 13-15 could also be utilized for determination of the
relative axial stereochemistry. For derivatives (6aR,aS)-13,
(6aR,aS)-14, and (6aR,aS)-15 a consistent upfield shift of the
methyl protons was observed. This effect is most probably due
to the induced field of the aromatic C-ring system, which causes
the aromatic methyl group, positioned close in space to the
C-ring, to be shifted upfield.
(13) Moreover, this sterical interaction is also likely to be the cause
of an unusual deviation in the C11-C1′ bond. The carbon atom
C1′ in (6aR,aR)- and (6aR,aS)-14 is located 0.231(8) and 0.252(7)
Å, respectively, out of a least-squares plane containing C7a, C8,
C9, C10, C11, and C11a. In addition, the C11-C1′ bond deviates
out of the aromatic plane of the A-ring, the torsion angles τ3-
(C9-C10-C11-C1′) and τ4(C7a-C11a-C11-C1′) in (6aR,aR)-
14 being -172° and 169°, respectively, and in (6aR,aS)-14 they
are τ3 ) -171° and τ4 ) 168°. In (6aR,aS)-14, which has the
slightly larger distortion, the bulky methyl group is positioned
close to the aporphine skeleton, while (6aR,aR)-14 has a cyano
group in the equivalent position. This supports the idea of
sterical interactions being the main factors causing the described
changes in the solid-state conformations of these atropisomeric
(R)-aporphines. Minimization (MM3)17 of the two solid-state
conformations in their nonprotonated form resulted in conforma-
tions in which the deviation of the C11-C1′ bond is smaller and
the torsion angle between the A- and C-rings (τ2) is slightly
larger than in the solid-state conformations. Ab initio minimiza-
tions at the RHF/6-31G* level18 of the solid-state conformation
of (6aR,aR)- and (6aR,aS)-14 gave similar C11-C1′ bond and
torsion angles as found in the MM3 calculated conformations.
Hence, the larger deviations of the C11-C1′ bond and the
smaller τ2 values observed in the solid-state conformations might
be effects due to crystal packing.
(14) For stability of atropisomers, see for example: Eliel, E. L.; Wilen,
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