R-(-)-N-alkyl-11-hydroxy-10-hydroxymethyl- and 10-methyl-aporphines as 5-HT1A receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2007.05.057

Several N-substituted-11-hydroxy-10-hydroxymethyl- and 11-hydroxy-10-methylaporphines were synthesized and their binding affinities at dopamine D₁ and D₂ receptors and serotonin 5-HT_1A and 5-HT_2A receptors in rat forebrain tissue were evaluated. Tested compounds displayed moderate to high affinity to 5-HT_1A receptors but low affinity to D₁ and D₂ receptors. The most potent novel 5-HT_1A agent was R-(-)-N-methyl-10-hydroxymethyl-11-hydroxyaporphine.

Full text of DOI:10.1016/j.bmcl.2007.05.057

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4128–4130
R-(À)-N-alkyl-11-hydroxy-10-hydroxymethyl-
and 10-methyl-aporphines as 5-HT1A receptor ligands
Yu-Gui Si,a Matthew P. Gardner,b Frank I. Tarazi,b
Ross J. Baldessarinib and John L. Neumeyera,*
aAlcohol Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
bMailman Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
Received 12 April 2007; revised 16 May 2007; accepted 17 May 2007
Available online 23 May 2007
Abstract—Several N-substituted-11-hydroxy-10-hydroxymethyl- and 11-hydroxy-10-methylaporphines were synthesized and their
binding affinities at dopamine D1 and D2 receptors and serotonin 5-HT1A and 5-HT2A receptors in rat forebrain tissue were eval-
uated. Tested compounds displayed moderate to high affinity to 5-HT1A receptors but low affinity to D1 and D2 receptors. The most
potent novel 5-HT1A agent was R-(À)-N-methyl-10-hydroxymethyl-11-hydroxyaporphine.
Ó 2007 Elsevier Ltd. All rights reserved.
R-Apomorphine, first synthesized in 1869, is an agonist
on central dopamine (DA) D1 and D2 receptors.1 Small
changes in the structure of apomorphine can lead to ma-
jor changes in pharmacological profiles.2 For example,
elimination of the 10-hydroxy group of apomorphine
produced a dopamine DA D1 receptor antagonist.3 Can-
non reported that replacement of the C10-hydroxy moi-
ety with a methyl group resulted in potent binding
affinity at the serotonin (5-hydroxytryptamine) 5-HT1A
receptor but low affinity at DA receptors.4 A previously
prepared series of 10-substituted-11-oxygenated R-(À)-
aporphines also lacked DA receptor affinity but showed
potent and selective affinity toward the 5-HT1A recep-
tor.5 Hedberg proposed that the selective serotonin
receptor affinity of these aporphines appears to be due
to a C10-methyl group, and a binding-site model sug-
gested the presence of a ‘methyl pocket’ in the 5-HT1A
receptor binding site.5c In contrast, the C10-methyl
group of these aporphines was not accommodated by
a binding-site model for DA receptors.5
(D1 and D2) and 5-HT (5-HT1A and 5-HT2A) receptors
(Fig. 1) .
R-(À)-10-methyl-11-hydroxyaporphine 2 was synthe-
sized starting from morphine by a procedure reported
by Hedberg.5b Triflation of the 3-hydroxy moiety of
morphine followed by a palladium-catalyzed coupling
reaction led to 8. Acid-catalyzed rearrangement of 8
yielded the desired aporphine 2 (Scheme 1). Scheme 2
shows the synthesis of 2-methoxy-10-methyl-11-hydro-
xy-aporphines 3 and 4. Thebaine 9 and N-n-propylnort-
hebaine 10 were O-demethylated to 11 and 12,
respectively, using the procedure reported by Coop,6
and then O-triflated to produce compounds 13 and 14.
A palladium-catalyzed coupling reaction of 13 and 14
with Sn(Me)4 gave 15 and 16, followed by their acid-cat-
alyzed rearrangement produced target compounds 3 and
4.5a The synthesis of 11-hydroxy-10-hydroxymethyla-
X
2
To develop additional insight into the importance of
C10 as well as N-substituents in aporphines for 5-HT
and DA receptor affinity, we synthesized several N-al-
kyl-11-hydroxy-10-hydroxymethyl- and 11-hydroxy-10-
methylaporphines and evaluated their affinity at DA
N
H
N
H
1
N
H
R1
R
Me
HO
Me
HO
HO
HO
HO
11
10
2 X = H, R = Me
3 X = OMe, R = Me
4 X = OMe, R = n-Pr
5 R1 = Me
6 R1 = n-Pr
1 (R)-Apomorphine
Keywords: Aporphines, Binding affinities; 5-HT1A receptor ligands.
*
Figure 1. Structures of aporphine analogs.
Corresponding author. E-mail: jneumeyer@mclean.harvard.edu
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.057

Y.-G. Si et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4128–4130
4129
N
N
N
N
H
H
H
b
H
a
c
HO
HO
O
OH
TfO
O
Me
OH
O
OH
H3C
Morphine.HCl
7
8
2
Scheme 1. Reagents: (a) PhNTf2, Et3N, CH2Cl2, 90%; (b) Me4Sn, (Ph3P)PdCl2, PPh3, LiCl, DMF, 75%; (c) MeSO3H, 65%.
MeO
R
R
R
R
N
N
N
N
N
R
a
H
c
b
d
HO
MeO
O
HO
OMe
TfO
O
O
Me
OMe
O
OMe
OMe
H3C
9 R = Me
10 R = -Pr
11 R = Me
12 R = -Pr
13 R = Me
15 R = Me
16 R = -Pr
3 X = OMe, R = Me
4 X = OMe, R = -Pr
n
n
14 R = -Pr
n
n
n
Scheme 2. Reagents: (a) L-selectride, THF, 23–28%; (b) PhNTf2, Et3N, CH2Cl2, 90–93%; (c) Me4Sn, (Ph3P)2PdCl2, PPh3, LiCl, DMF, 41–50%; (d)
MeSO3H, 45–50%.
N
N
R1
N
R1
R1
a
b
H
H
H
HO
HO
HO
HOH2C
OHC
17 R1 = Me
18 R1 =
-Pr
5 R1 = Me
6 R1 =
-Pr
19 R1 = Me
20 R1 =
-Pr
n
n
n
Scheme 3. Reagents: (a) MeMgBr, HMPA, (HCHO)n, benzene, 85–91%; (b) NaBH4, MeOH, 90–92%.
porphines 5 and 6 is shown in Scheme 3. We synthesized
the R-(À)-enantiomer of 11-hydroxyaporphines 17 and
18 using a previously reported procedure.7 Ortho-formy-
lation of the 11-hydroxy aporphines 17 and 18 employed
a modification of Cannon’s procedure4b and afforded
the desired products 19 (85%) and 20 (91%) in high
yields, followed by reduction of 19 and 20 with NaBH4
to produce the target compounds 5 and 6. Spectral (1H
NMR and 13C NMR) data and combustion analysis for
the target compounds were consistent with their pro-
posed structures.8
ring enhances affinity to DA receptors, whereas analo-
gous methyl or hydroxymethyl substitution enhances
interactions with the 5-HT1A receptor. Of note, the 10-
hydroxymethyl-substituted compound 5 displayed 100-
fold higher 5-HT1A receptor affinity (Ki = 2.4 nM) than
the 10-methyl substituted compound 2 (Ki = 216 nM),
suggesting that a 10-methyl group is not required for
affinity to the 5-HT1A receptor. The 2-methoxy group
in compound 3 seems to increase the affinity to
5-HT1A receptors (Ki = 21.5 nM) 10-fold higher than
compound 2 (Ki = 216 nM). That the 10-hydroxymethyl
compounds 5 and 6 were inactive at DA receptors sup-
ports the impression that a 10-hydroxymethyl group is
not required for high DA-receptor activity and that
the interaction of 10-hydroxymethylaporphines with
DA receptors does not involve hydrogen bonding. We
also evaluated compounds 3 and 5 for affinity to 5-
HT2A receptors and found 108-fold and 57-fold lower
potency than at 5-HT1A receptors, respectively (for com-
pound 5: Ki = 137 vs 2.4 nM; for 3: Ki = 271 vs 2.5 nM).
It is worthy to note that the N-propyl substitution is pre-
ferred over N-methyl substitution in the interaction with
DA receptors.10 In contrast N-methyl substitution
(Ki = 2.4 for compound 5 at 5-HT1A; Ki = 21.5 for com-
pound 3 at 5-HT1A) is preferred in the interaction with
5-HT receptor than the N-n-propyl substitution
(Ki = 375 for compound 6 at 5-HT1A; Ki = 480 for com-
pound 4 at 5-HT1A).
The affinities of compounds 2–6 for DA (D1 and D2)
and 5-HT (5-HT1A and 5-HT2A) receptors were assessed
using competitive binding assays with membrane
homogenates of whole rat brain tissue (5-HT1A and 5-
HT2A) or rat striatal tissue (D1 and D2). The following
tritiated radioligands were used: [3H]SCH23390 (D1),
[3H]nemonapride (D2), [3H]8-OH-DPAT (5-HT1A),
and [3H]ketanserin (5-HT2A).9 The results are summa-
rized in Table 1.
The N-substituted 11-hydroxy-10-hydroxylmethyl apor-
phine 5 and 11-hydroxy-2-methoxy-10-methyl congener
3 displayed selective and potent affinity for the serotonin
5-HT1A receptor but low affinity at DA receptors D1
and D2 (Table 1). These findings support the proposal
that ortho-dihydroxy substitution in the aporphine D

4130
Y.-G. Si et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4128–4130
Table 1. Affinities (Ki) for rat brain D1, D2, 5-HT1A, and 5-HT2A receptors
Compound
Ki (nM)
[3H]8-OH-DPAT (5-HT1A
[3H]SCH23390 (D1)
[3H]nemonapride (D2)
)
[3H]Ketanserin (5-HT2A
)
1
2
3
4
5
6
214 18a
9650 1250
1780 320
2790 640
1390 160
1980 380
13 2a
11500 1900
3760 760
1350 250
7000 850
6060 1110
296 15b
216 40
21.5 2.7
480 62
2.4 0.4
375 84
—
—
271 19
—
137 12
—
a From Ref. 7.
b From Ref. 5c.
1H), 3.08–3.00 (m, 3H), 2.75 (dd, J = 3.3 and 16.5 Hz,
1H), 2.55–2.45 (m, 2H), 2.52 (s, 3H), 2.28 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 150.8, 135.6, 135.4, 133.8,
131.5, 129.6, 127.6, 126.5, 123.6, 123.5, 120.9, 119.9, 62.39,
52.9, 44.0, 34.9, 29.1, 16.1; Anal. Calcd for C18H19NO: C,
71.63; H, 6.68; N, 4.64. Found: C, 71.34; H, 6.65; N, 4.60.
In addition, both 10-methyl and 10-hydroxymethyl
substituted 11-hydroxyaporphines displayed high affin-
ity toward serotonin 5-HT1A receptors but very low
affinity at DA (D1 and D2) receptors. Finally, the N-
methyl-substituted 11-hydroxy-10-methyl- and 10-
hydroxymethyl-aporphines were more potent than the
N-n-propyl analogs at 5-HT1A receptors.
1
Compound 3: mp (HCl salt) 183–185 °C; H NMR (base,
300 MHz, CDCl3) d 7.50 (d, J = 2.7 Hz, 1H), 7.00 (d,
J = 7.5 Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.61 (d,
J = 2.4 Hz, 1H), 3.82 (s, 3H), 3.24–3.00 (m, 4H), 2.72
(dd, J = 3.0 and 16.2 Hz, 1H), 2.56–2.47 (m, 2H), 2.52 (s,
3H), 2.29 (s, 3H); 13C NMR (base, 75 MHz, CDCl3) d
158.1, 150.8, 135.9, 135.0, 132.6, 129.7, 123.4, 120.1, 111.9,
110.3, 109.8, 62.1, 55.2, 53.0, 44.0, 35.3, 29.5, 16.1; Anal.
Calcd for C19H22ClNO2ÆH2O (salt): C, 65.23; H, 6.91; N,
4.00. Found: C, 64.88; H, 6.56; N, 3.85. Compound 4: mp
(HCl salt) 159–160 °C; 1H NMR (base, 300 MHz, CDCl3)
d 7.48 (d, J = 2.1 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.78
(d, J = 7.5 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 3.82 (s, 3H),
3.31–2.39 (m, 9H), 2.30 (s, 3H), 1.67–1.54 (m, 2H), 0.96 (t,
J = 7.5 Hz, 3H); 13C NMR (base, 75 MHz, CDCl3) d
158.1, 150.8, 136.0, 135.4, 132.8, 129.7, 123.4, 120.7, 120.0,
111.9, 110.2, 59.5, 56.4, 55.2, 48.9, 35.2, 29.6, 19.5, 16.1,
12.1; Compound 5: mp (HCl salt) >250 °C; (free base)
Acknowledgments
This work was supported by the Branfman Family
Foundation (to J. L. N. and R. J. B.), HD-052752 (to
FIT), by the Bruce J. Anderson Foundation, and the
McLean Private Donors Neuropsychopharmacology
Research Fund (R. J. B.). Morphine and thebaine were
generously supplied by Mallinkrodt Inc.
References and notes
1. Baldessarini, R. J.; Kula, N. S.; Zong, R.; Neumeyer, J. L.
Eur. J. Pharmacol. 1994, 254, 199.
1
203–205 °C; H NMR (base, 300 MHz, DMSO-d6) d 8.97
(br, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H),
7.07 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.82 (d,
J = 7.2 Hz, 1H), 5.74 (br, 1H), 4.66 (s, 2H), 3.15–2.90 (m,
4H), 2.7 (m, 1H), 2.44 (s, 3H), 2.42–2.25 (m, 2H); 13C
NMR (base, 75 MHz, DMSO-d6) d 152.2, 136.3, 134.7,
132.5, 131.5, 127.4, 126.8, 126.3, 125.7, 125.6, 121.5, 119.4,
61.9, 60.9, 52.4, 43.8, 34.5, 28.8; Anal. Calcd for
C18H19NO2ÆHClÆH2O (salt): C, 64.38; H, 6.50; N, 4.17.
Found: C, 63.83; H, 6.01; N, 4.09. Compound 6:(free base)
2. Zhang, A.; Zhang, Y.; Branfman, A. R.; Baldessarini, R.
J.; Neumeyer, J. L. J. Med. Chem. 2007, 50, 171.
3. Schaus, J. M.; Titus, R. D.; Foreman, M. M.; Mason, N.
R.; Truex, L. L. J. Med. Chem. 1990, 33, 600.
4. (a) Cannon, J. G.; Mohan, P.; Bojarski, J.; Long, J. P.;
Bhatnagar, R. K.; Leonard, P. A.; Flynn, J. R.; Chatter-
jee, T. K. J. Med. Chem. 1988, 31, 313; (b) Cannon, J. G.;
Moe, S. T.; Long, J. P. Chirality 1991, 3, 19.
5. (a) Hedberg, M. H.; Johansson, A. M.; Hacksell, U. J.
Chem. Soc., Chem. Commun. 1992, 845; (b) Hedberg, M.
H.; Johansson, A. M.; Nordvall, G.; Yliniemela¨, A.; Li,
H.-B.; Martin, A. R.; Hjorth, S.; Unelius, L.; Sundell, S.;
Hacksell, U. J. Med. Chem. 1995, 38, 647; (c) Hedberg, M.
H.; Jansen, J. M.; Nordvall, G.; Hjorth, S.; Unelius, L.;
Johansson, A. M. J. Med. Chem. 1996, 39, 3491.
6. Coop, A.; Lewis, J. W.; Rice, K. C. J. Org. Chem. 1996,
61, 6774.
1
160–161 °C; H NMR (base, 300 MHz, CDCl3) d 8.16 (d,
J = 7.8 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.05 (d,
J = 7.5 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.72 (d,
J = 7.8 Hz, 1H), 4.85 (ab, J = 12.9 and 36.0 Hz, 2H),
3.35–2.46 (m, 9H), 1.60 (m, 2H), 0.96 (t, J = 7.5 Hz, 3H);
13C NMR (base, 75 MHz, CDCl3) d 153.8, 138.4, 133.1,
131.8, 127.7, 126.6, 126.3, 126.1, 124.5, 122.3, 119.6, 119.2,
65.0, 59.7, 56.5, 49.1, 35.0, 29.2, 19.5, 12.3; Anal. Calcd for
C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.03;
H, 7.52; N, 4.50.
7. Csutoras, C.; Zhang, A.; Zhang, K.; Kula, N. S.;
Baldessarini, R. J.; Neumeyer, J. L. Bioorg. Med. Chem.
2004, 12, 3553.
9. Kula, N. S.; Baldessarini, R. J.; Kebabian, J. W.;
Bakthavachalam, V.; Xu, L. Eur. J. Pharmacol. 1997,
331, 333.
10. Menon, M. K.; Clark, W. G.; Neumeyer, J. L. Eur. J.
Pharm. 1978, 52, 1.
8. Compound 2: mp (free base) 270–271 °C; 1H NMR
(300 MHz, CDCl3) d 7.88 (d, J = 8.1 Hz, 1H), 7.25 (dd,
J = 7.5 and 7.5 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 7.00 (d,
J = 7.8 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 3.23–3.14 (m,