Synthesis and binding studies of 2-O- and 11-O-substituted N-alkylnoraporphines

Article abstract of DOI:10.1016/j.bmcl.2008.06.016

We synthesized several novel 2-O- or 11-O-substituted N-alkylnoraporphines and assessed their affinities at dopamine D₁ and D₂, and serotonin 5-HT_1A receptors in rat forebrain tissue. Tested compounds displayed moderate to high affinities to D₂ receptors but low affinities to D₁ and 5HT_1A receptors. The findings accord with previous evidence of a lipophilic cavity on the surface of the D₂ receptor to accommodate N-alkyl moieties of aporphines. The most D₂-potent (K_i = 97 nM) and selective novel agent (>100-fold vs. D₁ and 5-HT_1A sites) was R(-)-2-(2-hydroxyethoxy)-11-hydroxy-N-n-propylnoraporphine (compound 11).

Full text of DOI:10.1016/j.bmcl.2008.06.016

Bioorganic & Medicinal Chemistry Letters 18 (2008) 3971–3973
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and binding studies of 2-O- and 11-O-substituted
N-alkylnoraporphines
Yu-Gui Si, Matthew P. Gardner, Frank I. Tarazi, Ross J. Baldessarini, John L. Neumeyer *
Alcohol Drug Abuse Research Center and Mailman Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We synthesized several novel 2-O- or 11-O-substituted N-alkylnoraporphines and assessed their affinities
Received 15 May 2008
Revised 3 June 2008
Accepted 4 June 2008
Available online 10 June 2008
at dopamine D
played moderate to high affinities to D
ings accord with previous evidence of a lipophilic cavity on the surface of the D
accommodate N-alkyl moieties of aporphines. The most D -potent (K = 97 nM) and selective novel agent
1
and D
2
, and serotonin 5-HT1A receptors in rat forebrain tissue. Tested compounds dis-
receptors but low affinities to D and 5HT1A receptors. The find-
receptor to
2
1
2
2
i
(
(
>100-fold vs. D
compound 11).
1
and 5-HT1A sites) was R(À)-2-(2-hydroxyethoxy)-11-hydroxy-N-n-propylnoraporphine
Keywords:
Aporphines
Dopamine D1
Dopamine D2
Binding affinities
Ó 2008 Elsevier Ltd. All rights reserved.
The centrally active, dopaminergic, catecholaporphine R(À)-
apomorphine-HCl (APO) is approved for the treatment of Parkin-
son’s disease and erectile dysfunction, but its poor oral bioavail-
ability owing to susceptibility to oxidation and O-methylation of
the 10,11-catechol moiety limits its clinical utility (Fig. 1). Many
aporphine analogues have been synthesized and evaluated for po-
tency and selectivity of their interactions at central dopamine (DA)
X
2
A
D
B
N
H
1
N
H
R
Me
C
HO
1
HO 11
HO 10
2
a R = Me, X = OMe
2b R = Pr, X = OMe
c R-(-)-11-OH-NPa(R = Pr, X = H)
D
2
receptors in an effort to increase oral activity and extend dura-
1
R-(-)-APO
2
2
tion of action. Several 11-monohydroxy-aporphines have shown
similar neuropharmacological properties to 10,11-catecholapor-
Figure 1. Structures of potent aporphine analogues.
phines, including high potency and selectivity for DA D
2
receptors
3
(Fig. 1). Moreover, 11-hydroxyaporphines, and especially their
esters, have more prolonged behavioral arousal-inducing activity
with far superior oral bioavailability. Structure-activity relation-
ships of 2-substituted aporphines suggest their potential to
selectivity of 2-methoxy-11-monohydroxy-substituted apor-
4
phines. D receptor affinity is preferred with N-methyl, and D is
1
2
6
preferred with an N-n-propyl substituent (Fig. 1). To further de-
velop insights into the structure-activity relationships of 2- and
11-substituted aporphines, we now report on the design and syn-
2
increase selectivity and affinity at DA D receptors. A number of
2
-substituted aporphines have been synthesized in several labora-
5
tories including ours. Such aporphines can be 2-substituted with
aryl,
thesis of six novel aporphines, with their potencies at DA D and D1
2
5
a,b
5c
5d
5e–h
O-alkyl, methylthio, or halogen.
substituents. The
receptors as well as serotonin 5-HT1A receptors in mammalian
neuropharmacological characteristics of these analogues point to
the existence of a lipophilic cleft or region on the surface of DA
forebrain tissue.
We synthesized 2-methoxyaporphine and 2-methoxy-N-pro-
pylnoraporphine starting from thebaine (Scheme 1) as starting
materials. Then 2-methoxy-11-hydroxyaporphines were prepared
D
2
receptor proteins, corresponding to 2-substituents of apor-
phines, the lipophilicity of which seems more important than their
spatial parameters.
6
according to a published procedure in 7 steps, followed by
We recently reported the synthesis and evaluation of N-alkyl-2-
methoxy-11-hydroxynoraporphines, with additional evidence that
N-alkyl substituents have a major effect on D affinity and D /D
2 2 1
removal of the 11-hydroxy group to yield the compounds 4a and
4b (Scheme 1). We also synthesized 2-hydroxy-11-alkyloxyapor-
phines 8a–c from thebaine or oripavine (Scheme 2). 3-O-Triflation
7
of oripavine followed by acid-catalyzed rearrangement and
2
-demethylation led to the 2,11-dihydroxy-10-O-trifluoromethyl-
*
Corresponding author. Tel.: +1 617 855 3388; fax: +1 617 855 2519.
E-mail address: jneumeyer@mclean.harvard.edu (J.L. Neumeyer).
sulfonyl aporphine 6. Alkylation of the 2,11-dihydroxy-10-O-tri-
0
960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.016

3
972
Y.-G. Si et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3971–3973
MeO
MeO
MeO
Pd/C, Mg,
NH OAc
Me
N
7steps
ref.6
PhNTf ,Et N
2
2
3
N
N
N
R
CH Cl
R
4
R
2
H
H
H
HO
TfO
52-73%
8
4-90%
MeO
O
OMe
Thebaine
2
2
a R = Me
b R = Pr
3a R = Me
3b R = Pr
4a R = Me
4b R = Pr
Scheme 1. Synthesis of compounds 4a and 4b.
Me
HO
Me
Me
N
N
N
MeSO H,
90-100 C, 2hr
N
H
3
o
Me
L-selectride
HO
TfO
O
75%
MeO
O
HO
OMe
OMe
O
OMe
TfO
Thebaine
Oripavine
5
6
1
R I, K CO
2
3
DMF
HO
HO
Pd/C, Mg,
N
N
Me
Me
NH OAc
4
H
H
1
1
R O
R O
TfO
7a R1 = Et
7b R = Pr
7c R = CH CH OH
8
8
8
a R1 = Et
1
1
b R = Pr
1
1
c R = CH CH OH
2
2
2
2
Scheme 2. Synthesis of compounds 8a, 8b and 8c.
fluoromethylsulfonyl aporphine 6 with alkyl iodide in N,N-dimeth-
ylformamide gave only the 11-alkylated products 7a–c. Further
Pd/C-catalyzed reduction of 7a–c with Mg metal in MeOH at room
temperature provided compounds 8a–c. 2-O-(2-hydroxyethyl)-11-
hydroxy-N-n-propylnoraporphine 11 was synthesized from theba-
ine (Scheme 3). The triflate 9 was prepared following our published
5-HT1A receptor. Blocking the 11-hydroxy group with an alkyl, but
adding a hydroxy substituent on the 2-position also decreased the
affinities at DA and 5-HT receptors. These findings support the pro-
posal that 11-hydroxy substitution in aporphines (homologous to
critical position-3 of DA) is required for dopaminergic activity as
reflected in affinity at DA, and is also required for affinity at some
5-HT receptors. Compared with the potent compound R-(À)-2-
methoxy-11-hydroxy-N-n-propylnoraporphine, introduction of a
hydrophilic group such as a hydroxyethoxy at the 2-position re-
6
procedure. Acid-catalyzed rearrangement of 9 in the presence of
5
c
glycol followed by Pd/C-catalyzed reduction gave compound
1
13
1
1. Spectral ( H NMR and C NMR) data and combustion analysis
for the target compounds were consistent with their proposed
structures.
duced affinity at D
selectivity by >3-fold. These observations support previous find-
ings indicating that a lipophilic cavity is present on the surface of
the D receptor at a location that accommodates 2-substituents
2 2
receptors by half, while increasing the D -over
8
D
1
The receptor affinities of the six novel compounds 4a, 4b, 8a–c,
1
1 at D
2
and D
1
DA receptors and the serotonin 5-HT1A receptor
2
5
were assessed using competitive radioreceptor binding assays with
membrane-containing homogenates of rat corpus striatum tissue,
following procedures reported in detail previously.4 The results
are summarized in Table 1.
The findings indicate that removal of the 11-hydroxy group
from the 2-methoxy-11-hydroxy-N-alkylaporphines decreased
affinity at DA receptors, and afforded low affinity for the serotonin
of aporphines.
The neuropharmacological profiles of the newly synthesized 2-
substituted and 11-substituted aporphines, together with the pre-
viously reported characteristics of 2-substituted-11-monohydr-
oxyaporphines support the following tentative conclusions: (1)
The presence of a single hydroxy group in 11-position is both nec-
2
essary and sufficient to confer affinity and activity at DA D recep-
O
O
Me
HO
OH
HO
Pr
Pr
N
N
HOCH
2
CH
2
N
N
Pr
5
steps
MeSO H,
H
H
3
o
HO
Pd/C, Mg, HO
9
0-95 C, 30 min
ref. 6
OMe
NH OAc
4
MeO
O
TfO
O
TfO
OMe
51%
73%
Thebaine
9
10
11
Scheme 3. Synthesis of compound 11.

Y.-G. Si et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3971–3973
3973
Table 1
i 1 2
Affinities (K ) for rat brain D , D , and 5HT1A receptors
X
N
R
H
R1
R2
R1
R2
X
K
a
(nM)
Compound
R
i
2 1
D /D
D
1
D
2
5HT1A
1b
Me
Me
Pr
Pr
Me
Pr
Me
Me
Me
Pr
OH
OH
OH
OH
H
H
OEt
OPr
OH
H
H
H
H
H
H
H
H
H
H
1010 ± 105
1.9 ± 0.5
—
—
—
—
532
0.19
38.4
24.5
1.8
>43
5.7
7.8
2
2
2
4
4
8
8
8
1
ab
OMe
OMe
H
OMe
OMe
OH
OH
OH
OCH
46.0 ± 2.8
1690 ± 130
699 ± 118
1300 ± 250
>10,000
3680 ± 760
1810 ± 380
>10,000
>10,000
235 ± 32
44.0 ± 8.3
28.5 ± 12.8
731 ± 155
230 ± 35
641 ± 110
230 ± 40
3340 ± 690
97 ± 18
b
b
c
c
a
b
a
b
c
2660 ± 400
1600 ± 280
432 ± 99
—
289 ± 39
—
OCH
OH
2
CH
2
OH
3.0
>103
1
2
2
CH OH
a
b
c
3
3
3
Radioligands: D
Data from Ref. 6.
Data from Ref. 4.
1
: [ H]SCH23390; D
2
: [ H]nemonapride; 5HT1A: [ H]8-OH-DPAT.
tors; (2) for the 2-position of aporphines, several factors contribute
to dopaminergic activity, including lipophilicity, steric effects, and
hydrogen-bonding of the 2-substituent. However, the lipophilicity
of the substituent appears to be more important than the other fac-
4428; (h) Zhang, A.; Csutoras, C.; Zong, R.; Neumeyer, J. L. Org. Lett. 2005, 7,
239.
Si, Y.-G.; Gardner, M. P.; Tarazi, F. I.; Baldessarini, R. J.; Neumeyer, J. L. J. Med.
Chem. 2008, 51, 983.
3
6
.
7. Coop, A.; Lewis, J. W.; Rice, K. C. J. Org. Chem. 1996, 61, 6774.
1
8.
Compound 4a: mp (HCl salt) 248–250 °C; H NMR (base, 300 MHz, CDCl
.69 (d, J = 7.5 Hz, 1H), 7.34–7.23 (m, 3H), 7.12 (d, J = 2.6 Hz, 1H), 6.62 (d,
J = 2.6 Hz, 1H), 3.84 (s, 3H), 3.25–3.03 (m, 4H), 2.75–2.50 (m, 3H), 2.55 (s,
3H); 13
NMR (base, 75 MHz, CDCl 158.4, 135.6, 134.9, 134.6, 134.1,
28.4, 127.6, 127.2, 126.3, 123.7, 112.3, 108.1, 61.6, 55.2, 53.4, 43.8, 34.4,
9.3; Anal. calcd for C18 O: C, 70.91; H, 6.69; N, 4.59. Found:
19NOÁHClÁ0.2H
3
) d
tors; (3) D
substituent, whereas D
2
potency and activity are optimal with an N-n-propyl
potency is preferred with N-methyl substi-
7
1
tuent but also greatly affected by the character of 2- and 11-sub-
stituents. Further conformation of these conclusions must await
the preparation of additional aporphine analogues substituted in
the 2, 11, and 6N-positions.
C
3
) d
1
2
H
2
1
C, 70.67; H, 6.64; N, 4.52. Compound 4b: mp (HCl salt): 234–236 °C; H NMR
(base, 300 MHz, CDCl ) d 7.68 (d, J = 7.5 Hz, 1H), 7.34–7.23 (m, 3H), 7.10 (d,
J = 2.6 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 3.83 (s, 3H), 3.43 (dd, J = 13.8 and
.9 Hz, 1H), 3.22–3.06 (m, 3H), 2.92 (m, 1H), 2.74–2.41 (m, 4H), 1.67–1.56
3
3
13
Acknowledgments
3
(m, 2H), 0.97 (t, J = 7.2 Hz, 3H); C NMR (base, 75 MHz, CDCl ) d 158.3, 135.8,
1
5
6
35.2, 134.9, 134.3, 128.4, 127.6, 127.2, 127.0, 123.7, 112.3, 108.1, 58.9, 56.1,
5.2, 49.3, 34.3, 29.4, 19.2, 12.1; Anal. calcd for O: C,
23NOÁHClÁ1.4H
7.75; H, 7.56; N, 3.95. Found: C, 67.88; H, 7.23; N, 3.59. Compound 8a: mp
C
20
H
2
This work was supported by Grant from the Branfman Family
Foundation (to J.L.N. and R.J.B.), NIH HD-052752 (to F.I.T.), by the
Bruce J. Anderson Foundation, and the McLean Private Donors Neu-
ropsychopharmacology Research Fund (R.J.B.). Thebaine was gen-
erously donated by Mallinkrodt Inc.
1
(HCl salt) 248–250 °C; H NMR (base, 300 MHz, CDCl ) d 7.63 (d, J = 2.4 Hz,
3
1
1
2
H), 7.12 (dd, J = 7.8 and 7.5 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.81(d, J = 7.8 Hz,
H), 6.32 (d, J = 2.4 Hz, 1H), 4.03 (m, 1H), 3.93 (m, 1H), 3.12–2.90 (m, 4H),
13
.64–2.45 (m, 3H), 2.53 (s, 3H), 1.35 (t, J = 6.9 Hz, 3H);
C NMR (base,
75 MHz, CDCl ) d 155.9, 154.5, 137.8, 133.1, 132.6, 127.8, 125.8, 122.9, 120.6,
3
1
C
4
14.5, 113.8, 111.6, 64.1, 61.8, 53.0, 43.6, 35.2, 28.7, 14.7. Anal. calcd for
21NO O: C, 67.97; H, 6.68; N, 4.17. Found: C, 67.91; H, 6.76; N,
ÁHClÁ0.2H
.00. Compound 8b: mp (HCl salt) 186–188 °C;
) d 7.64 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.1 and 7.8 Hz, 1H), 6.84 (d,
19
H
2
2
References and notes
1
H
NMR (base, 300 MHz,
CDCl
3
1
.
(a) Neumeyer, J. L.; Baldessarini, R. J.; Booth, R. G., Sixth ed.. In Burger’s Medicinal
Chemistry and Drug Discovery; Abraham, D. J., Ed.; John Wiley & Sons: New York,
J = 7.8 Hz, 1H), 6.82(d, J = 8.1 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 3.93 (m, 1H),
3.81 (m, 1H), 3.13–2.90 (m, 4H), 2.64–2.46 (m, 3H), 2.53 (s, 3H), 1.81–1.74
(m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (base, 75 MHz, CDCl
2
003; Vol. 6, p 711. (Chapter 12); (b) Hsieh, G. C.; Hollingsworth, P. R.; Martino,
3
) d 156.14,
B.; Chang, R.; Terranova, M. A.; O’Neill, A. B.; Lynch, J. J.; Moreland, R. B.;
Donnelly-Roberts, D. L.; Kolasa, T.; Mikusa, J. P.; McVey, J. M.; Marsh, K. C.;
Sullivan, J. P.; Brioni, J. D. J. Pharmacol. Exp. Ther. 2004, 308, 330; (c) Subramony,
J. A. Mol. Pharm. 2006, 3, 380.
Zhang, A.; Zhang, Y.; Branfman, A. R.; Baldessarini, R. J.; Neumeyer, J. L. J. Med.
Chem. 2007, 50, 171.
Gao, Y.; Zong, R.; Campbell, A.; Kula, N. S.; Baldessarini, R. J.; Neumeyer, J. L. J.
Med. Chem. 1988, 31, 1392.
Csutoras, C.; Zhang, A.; Zhang, K.; Kula, N. S.; Baldessarini, R. J.; Neumeyer, J. L.
Bioorg. Med. Chem. 2004, 12, 3553.
154.4, 137.8, 133.1, 132.7, 127.8, 125.8, 122.9, 120.6, 114.6, 113.7, 111.5,
70.2, 61.8, 53.0, 43.6, 35.2, 28.7,22.5, 10.6. Anal. calcd for
C
20
H
23NO
N, 3.86. Compound 8c: mp (HCl salt) 189–191 °C; H NMR (base, 300 MHz,
CDCl ) d 7.75 (d, J = 1.8 Hz, 1H), 7.03 (dd, J = 7.8 and 7.5 Hz, 1H), 6.75 (d,
2
ÁHClÁ0.6H
2
O: C, 67.35; H, 7.07; N, 3.92. Found: C, 67.13; H, 6.97;
1
2.
3.
4.
5.
3
J = 7.5 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.47 (d, J = 1.8 Hz, 1H), 4.10 (m, 1H),
3.84 (m, 3H), 3.09–2.87 (m, 4H), 2.60–2.40 (m, 3H), 2.47 (s, 3H); 13C NMR
(base, 75 MHz, CDCl
121.0, 114.3, 114.0, 111.1, 69.9, 61.7, 60.8, 52.9, 43.4, 35.0, 28.7. Anal. calcd
for C19 21NO O: C, 62.38; H, 6.61; N, 3.83. Found: C, 62.36; H, 6.57;
ÁHClÁH
N, 3.65. Compound 11: mp (HCl salt) 178–180 °C (Dec);
300 MHz, CDCl ) d 7.60 (d, J = 2.6 Hz, 1H), 7.08 (t, J = 8.2 Hz, 1H), 6.85 (d,
3
) d 155.7, 154.3, 137.7, 133.2, 132.4, 127.9, 125.7, 122.6,
H
3
2
1
(a) Søndergaard, K.; Kristensen, J. L.; Palner, M.; Gillings, N.; Knudsen, G. M.;
Roth, B. L.; Begtrup, M. Org. Biomol. Chem. 2005, 3, 4077; (b) Sipos, A.; Kiss, B.;
Schmidt, É.; Greiner, I.; Berényi, S. Bioorg. Med. Chem. 2008, 16, 3773; (c) Sipos,
A.; Csutorás, C.; Berényi, S.; Uustare, A.; Rinken, A. Bioorg. Med. Chem. 2008, 16,
H NMR (base,
3
J = 7.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 4.06 (t,
J = 4.3 Hz, 2H), 3.94 (t, J = 4.3 Hz, 2H), 3.36 (m, 1H), 3.20–3.06 (m, 3H), 2.89
(m, 1H), 2.73–2.46 (m, 4H), 1.63–1.55 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13
C
4
563; (d) Tóth, M.; Berényi, S.; Csutorás, C.; Kula, N. S.; Zhang, K.; Baldessarini, R.
J.; Neumeyer, J. L. Bioorg. Med. Chem. 2006, 14, 1918; (e) Ramsby, S.; Neumeyer, J.
L.; Grigoriadis, D.; Seeman, P. J. Med. Chem. 1989, 32, 1198; (f) Neumeyer, J. L.;
Gao, Y.; Kula, N. S.; Baldessarini, R. J. J. Med. Chem. 1990, 33, 3122; (g)
Søndergaard, K.; Kristensen, J. L.; Gillings, N.; Begtrup, M. Eur. J. Org. Chem. 2005,
NMR (base, 75 MHz, CDCl
115.7, 112.5, 112.3, 69.1, 61.2, 59.0, 55.9, 48.8, 34.8, 28.8, 18.8, 11.9. Anal.
calcd for C21 25NO O: C, 62.26; H, 7.15; N, 3.46. Found: C, 62.26;
ÁHClÁ1.5H
H, 6.76; N, 3.48.
3
) d 156.8, 153.3, 138.1, 134.1, 132.9, 120.9 120.2,
H
3
2