Synthesis and neuropharmacological evaluation of esters of R(-)-N-alkyl-11-hydroxy-2-methoxynoraporphines

Article abstract of DOI:10.1016/j.bmcl.2008.11.025

We synthesized several esters of R(-)-N-alkyl-11-hydroxy-2-methoxynoraporphines, assessed their affinities at dopamine D₁ and D₂ receptors in rat forebrain tissue and quantified their effects on motor activity in normal adult male rats. Tested compounds displayed moderate to high affinities to D₂ receptors but low affinities to D₁ receptors. The most D₂-potent (K_i = 18.9 nM) and selective novel agent (>529-fold vs D₁ sites) was R(-)-2-methoxy-11-acetyloxy-N-n-propylnoraporphine (compound 4b). At moderate doses, the compound proved to have prolonged behavioral locomotor activity.

Full text of DOI:10.1016/j.bmcl.2008.11.025

Bioorganic & Medicinal Chemistry Letters 19 (2009) 51–53
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and neuropharmacological evaluation of esters
of R(À)-N-alkyl-11-hydroxy-2-methoxynoraporphines
Yu-Gui Si, Yong-Kee Choi, 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 esters of R(À)-N-alkyl-11-hydroxy-2-methoxynoraporphines, assessed their
Received 18 September 2008
Revised 31 October 2008
Accepted 10 November 2008
Available online 13 November 2008
1 2
affinities at dopamine D and D receptors in rat forebrain tissue and quantified their effects on motor
activity in normal adult male rats. Tested compounds displayed moderate to high affinities to D
tors but low affinities to D receptors. The most D -potent (K = 18.9 nM) and selective novel agent (>529-
fold vs D
sites) was R(À)-2-methoxy-11-acetyloxy-N-n-propylnoraporphine (compound 4b). At moder-
ate doses, the compound proved to have prolonged behavioral locomotor activity.
Ó 2008 Elsevier Ltd. All rights reserved.
2
recep-
1
2
i
1
Keywords:
Aporphine
Binding affinity
D dopamine receptor
2
Locomotor activity
Although R(À)-apomorphine-HCl (APO) is approved for the treat-
ment of Parkinson’s disease and erectile dysfunction, its clinical util-
ity is limited by poor oral bioavailability owing to susceptibility to
reacting the appropriate acid or anhydride with aporphines 2a
and 2b. Spectral ( H NMR and C NMR) data and combustion anal-
1
13
ysis for the target compounds were consistent with their proposed
7
oxidation and O-methylation of the 10,11-catechol moiety
structures.
1
(
Fig. 1). In order to improve oral activity and extend the duration
The receptor affinities of the four novel compounds 4a, 4b, 4c
of action, many novel aporphine analogues have been synthesized
2 1
and 4d at D and D receptors were assessed using competitive
and evaluated for potency and selectivity of their interactionsat cen-
radioreceptor binding assays with membrane-containing homoge-
nates of rat corpus striatum tissue and standard radioligands, fol-
lowing procedures reported in detail previously (Table 1).
2
tral dopamine (DA) D
2
receptors. Structure–activity relationships
5
(
SARs) of 2-substituted aporphines suggest their potential to in-
crease selectivity and affinity at DA D
2
receptors.3 Findings from
Based on radioreceptor affinities (Table 1), the esters of 2-meth-
our laboratory have shown that 11-monohydroxy-aporphines have
similar neuropharmacological properties to 10,11-catecholapor-
oxy-11-hydroxy-N-alkylaporphines present similar selectivity. D
2
potency and activity were optimal with an N-n-propyl versus N-
methyl substituent. Affinities of most esters of aporphines were
somewhat lower than that of the corresponding free 11-hydroxyl
aporphines. A surprising exception is R(À)-2-methoxy-11-acetyl-
phines, including high potency and selectivity for DA D
2
receptors
4
(Fig. 1). Moreover, 11-monohydroxyaporphines, and especially
their esters (Fig. 1, 3a and 3b) have more prolonged behavioral arou-
5
sal-inducing activity with superior oral bioavailability.
2
oxy-N-n-propylnoraporphine (4b). The affinity of 4b at D in-
We recently reported the synthesis and evaluation of N-alkyl-2-
methoxy-11-hydroxynoraporphines (Fig. 1, 2a and 2b). To further
improve oral activity and extend duration of action of these apor-
phine analogues, we now report the synthesis of four esters of such
creased compared with the analogous 11-hydroxy compound 2b
(from 44 nM to 18.9 nM). However, the R(À)-2-methoxy-11-vale-
6
ryloxy-N-n-propylnoraporhine (4c) had lower affinity at D
2
than
the 11-hydroxy analogue 2b (from 44 nM to 192 nM).
aporphines, with their potencies at dopamine (DA) D
receptors in mammalian forebrain tissue, and their potency in
stimulating motor activity in normal adult male rats.
2
and D
1
In vivo administration of 4b (MCL-515) produced long-lasting
effects on locomotor activity in adult rats. Scoring locomotor
8
activity increases over 24 h, induced by MCL-515 (4
n = 10), the valerate ester 4d (MCL-523; 4 mol/kg; n = 8), APO it-
self (4 mol/kg; n=17), or vehicle indicated that locomotor activity
lmol/kg;
2
-Methoxy-11-hydroxyaporphine 2a and 2-methoxy-11-hy-
l
droxy-N-propylnoraporphine 2b were prepared in 7 steps, starting
from thebaine (Scheme 1) according to a published procedure.
l
6
induced by the ester MCL-515 was more prominent than that in-
Representative esters (acetyl and valeryl) 4a–d were prepared by
duced by APO from 12 to 24 h after intraperitoneal (ip) injection
(Fig. 2). 4d (MCL-523) did not enhance locomotor activity through-
out the testing session. In contrast, it appeared to exhibit a long-
lasting sedative effect compared to vehicle-treated control rats
*
Corresponding author. Tel.: +1 617 855 3388; fax: +1 617 855 2519.
E-mail address: jneumeyer@mclean.harvard.edu (John L. Neumeyer).
0
960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.025

5
2
Y.-G. Si et al. / Bioorg. Med. Chem. Lett. 19 (2009) 51–53
MeO
2
X
A
B
N
N
H
N
H
N
H
Pr
R
1
Me
R
H
R1
O
R1
C
O
O
HO 11
HO
D
O
HO 10
1
4
a (MCL-514) R = Me, R = Me
3
a R = Me
b R =
-Bu
2
2
2
a R = Me, X = OMe
b R = Pr, X = OMe
c 11-OH-NPa (R = Pr, X = H)
1
3
n
4b (MCL-515) R = Pr, R = Me
1
R(-)-APO
1
4
4
c (MCL-516) R = Me, R =
n-Bu
1
d (MCL-523) R = Pr, R =
n-Bu
Figure 1. Structures of potent aporphine analogues.
R
N
Me
R
N
N
PhNTf2, Et N
3
CH2Cl2
L-selectride
THF
2
8%
HO
72-75%
O
OMe
MeO
O
TfO
OMe
O
OMe
8
8
a R = Me, Oripavine
b R = Pr
9
9
a R = Me
b R = Pr
5
Thebaine
MeSO H, 44-56%
3
1
2
. DEAD, Benzene;
. Py.HCl, MeOH
L-selectride 37%
THF
MeO
37%
N
R
H
Pr
N
NH
HO
R-I, K CO3
2
TfO
6
8%
MeO
O
OMe
MeO
O
10a R = Me
0b R = Pr
OMe
1
6
Northebaine
7
Pd/C, Mg,
NH OAc,MeOH
4
7
5-76%
MeO
MeO
HO
N
N
R
R
H
Ac O, Et N, DMAP
H
H C
3
O
O
2
3
7
2-82%
4
4
a R = Me
b R = Pr
2a R = Me
2b R = Pr
CH (CH ) COOH
3
2 3
DCC, DMAP, 76-90%
MeO
N
R
H
n-C H
O
O
4
9
4
4
c R = Me
d R = Pr
Scheme 1. Synthesis of compounds 4a, 4b, 4c, and 4d.

Y.-G. Si et al. / Bioorg. Med. Chem. Lett. 19 (2009) 51–53
53
Table 1
Affinities (K
References and notes
i
) for rat brain D
1
and D
2
receptors
a
CLogPd
1. (a) Neumeyer, J. L.; Baldessarini, R. J.; Booth, R. G. In Burger’s Medicinal Chemistry
and Drug Discovery; Abraham, D. J., Ed., 6th ed.; John Wiley & Sons: New York,
2003; pp 711–714 (Chapter 12, Vol. 6); (b) Hsieh, G. C.; Hollingsworth, P. R.;
Martino, 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.
Compound
K
i
(nM)
Selectivity
/D
D
1
D
2
D
1
2
b
b
1.9 ± 0.5b
235 ± 32
44.0 ± 8.3
28.5 ± 12.8
1
2
2
2
3
3
4
4
4
4
(APO)
a
b
c
a
b
a (MCL-514)
b (MCL-515)
c (MCL-516)
d (MCL-523)
1010 ± 105
46.0 ± 2.8
1690 ± 130
699 ± 118
532
0.2
38
2.49
3.26
4.10
4.14
4.16
5.75
3.27
4.11
4.64
5.70
b
b
b
c
c
24
2.
Zhang, A.; Zhang, Y.; Branfman, A. R.; Baldessarini, R. J.; Neumeyer, J. L. J. Med.
Chem. 2007, 50, 171.
c
c
>10,000
72.3 ± 6.8
>138
>58
3
>529
8
>20,000c
526 ± 59
>10,000
340 ± 65c
165 ± 39
18.9 ± 4.2
192 ± 53
89 ± 22
3. (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, 4563; (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, 4428; (h) Zhang, A.; Csutoras, C.;
Zong, R.; Neumeyer, J. L. Org. Lett. 2005, 7, 3239; (i) Si, Y.-G.; Gardner, M. P.; Tarazi,
F. I.; Baldessarini, R. J.; Neumeyer, J. L. Bioorg. Med. Chem. 2008, 18, 3971.
1480 ± 220
>10,000
>112
a
3
3
Radioligands: D
Data from Ref. 6.
Data from Ref. 5.
1
: [ H]SCH23390; D
2
: [ H]nemonapride.
b
c
d
Calculated by the ChemProp feature in CambridgeSoft ChemDraw Ultra, version
9
.0.1.
4.
5.
6.
7.
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.
Si, Y.-G.; Gardner, M. P.; Tarazi, F. I.; Baldessarini, R. J.; Neumeyer, J. L. J. Med.
Chem. 2008, 51, 983.
Compound 4a: mp (HCl salt) 156–158 °C; 1H NMR (300 MHz, CDCl
3
) d 7.41 (d,
J = 2.4 Hz, 1H), 7.20 (dd, J = 7.5 and 6.9 Hz, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.63 (d,
J = 1.8 Hz, 1H), 3.81 (s, 3H), 3.23–3.13 (m, 3H), 3.03 (dd, J = 11.4 and 6.0 Hz, 1H),
2
1
6
6
.74–2.50 (m, 3H), 2.55 (s, 3H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl
3
) d 169.1,
57.9, 147.3, 138.6, 134.4, 131.6, 127.9, 127.7, 127.0, 126.2, 122.1, 112.5, 111.4,
1.4, 55.2, 52.9, 43.9, 35.2, 29.4, 21.4; Anal. Calcd for C20 21NO O: C,
ÁHClÁ1.5H
2.18; H, 6.47; N, 3.63. Found: C, 62.57; H, 5.89; N, 3.61.
) d 7.39
d, J = 2.7 Hz, 1H), 7.26–7.17 (m, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.62 (d, J = 2.7 Hz,
H
3
2
1
Compound 4b: mp (HCl salt) 143–145 °C; H NMR (base, 300 MHz, CDCl
(
3
1H), 3.80 (s, 3H), 3.36 (dd, J = 13.5 and 3.6 Hz, 1H), 3.18–3.05 (m, 3H), 2.94–2.84
(
m, 1H), 2.74–2.68 (m, 1H), 2.59–2.33 (m, 3H), 2.30 (s, 3H), 1.66–1.54 (m, 2H),
0
1
4
.96 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl
34.9, 131.8, 128.4, 127.8, 127.1, 126.1, 122.0, 112.5, 111.4, 58.8, 56.4, 55.2,
8.9, 35.3, 29.6, 21.4, 19.5, 12.0. Anal. Calcd for C22 25NO O: C, 63.77;
ÁHClÁ1.5H
3
) d 169.1, 157.7, 147.2, 138.9,
H
3
2
H, 7.00; N, 3.38. Found: C, 64.00; H, 6.61; N, 3.27.
Compound 4c: mp (HCl salt) 196–198 °C; 1H NMR (base, 300 MHz, CDCl
d, J = 2.4 Hz, 1H), 7.26–7.16 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.61 (d, J = 2.4 Hz,
1H), 3.80 (s, 3H), 3.18–3.12 (m, 3H), 3.02 (dd, J = 11.4 and 5.4 Hz, 1H), 2.74–2.48
m, 5H), 2.55 (s, 3H), 1.75–1.65 (m, 2H), 1.46–1.33 (m, 2H), 0.93 (t, J = 7.2 Hz,
3
) d 7.39
(
Figure 2. Locomotor activity of APO, 4b (MCL-515), and 4d (MCL-523).
(
3
1
2
3
H); 13C NMR (75 MHz, CDCl
27.7, 127.1, 126.0, 122.2, 112.3, 111.8, 61.4, 55.1, 52.9, 43.9, 35.3, 34.4, 29.4,
3
) d 171.9, 157.8, 147.4, 138.6, 134.3, 131.6, 127.8,
.
.
6.7, 22.2, 13.6. Anal. Calcd for C23
3 2
H28NO HCl 1.75H O: C, 63.74; H, 6.69; N,
that was most prominent at 12–20 h after ip administration
Fig. 2).
The neurophamacological profiles of the newly synthesized
.23. Found: C, 63.65; H, 6.64; N, 3.17.
(
Compound 4d: mp (HCl salt) 178–180 °C (Dec); 1H NMR (base, 300 MHz, CDCl
3
) d
7.37 (d, J = 2.4 Hz, 1H), 7.25–7.16 (m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 6.30 (d, J = 2.4 Hz,
H), 3.79 (s, 3H), 3.36 (dd, J = 13.5 and 3.3 Hz, 1H), 3.16–3.06 (m, 3H), 2.93–2.84
m, 1H), 2.73–2.63 (m, 1H), 2.60–2.37 (m, 5H), 1.74–1.54 (m, 4H), 1.45–1.25 (m,
1
(
esters of 2-methoxy-11-hydroxyaporphines, together with previ-
ously reported characteristics of 11-monohydroxyaporphines and
their esters, support the tentative conclusion that esterification
of the single hydroxy group in the 11-position is an efficient
method to improve the bioavailability and duration of action of
such aporphines. Confirmation of this suggestion requires further
investigation.
13
2
H), 0.95 (t, J = 7.8 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H); C NMR (75 MHz, CDCl
171.9, 157.6, 147.3, 138.9, 134.8, 131.7, 128.3, 127.7, 127.2, 125.9, 122.0, 112.2,
11.7, 58.8, 56.4, 55.1, 48.9, 35.3, 34.3, 29.6, 26.7, 22.2, 19.5, 13.6, 12.0. Anal. Calcd
for C25 31NO O: C, 68.34; H, 7.52; N, 3.59. Found: C, 68.28; H, 7.89; N,
ÁHClÁ0.5H
.71.
3
) d
1
H
3
2
3
8. Locomotor activity of testing agents was monitored individually for 24 h by
using an infrared photobeam activity monitoring system (San Diego Instrument,
San Diego, CA) connected with a microcomputer. Behavioral experiments were
conducted in novel environment (17 Â 8 Â 8 in. transparent plastic cages with
4
 8 horizontal infrared beams), usually started at 11:00 AM and finished 11:00
Acknowledgments
AM next day with free access of food and water. Consecutive breaking of one
photobeam was counted as one score for locomotor activity. Scored data were
collected at 1, 4, 8, 12, 16 and 24 h after intraperitoneal (ip) injection of 4b
This work was supported by grant from the Branfman Family
Foundation (to J.L.N.), by the Bruce J. Anderson Foundation, and
the McLean Private Donors Neuropsychopharmacology Research
Fund (R.J.B.). Thebaine was generously donated by Mallinkrodt Inc.
(
MCL-515), 4d (MCL-523), apomorphine, or vehicle. Testing agents were
dissolved in 0.9% NaCl containing 2% dimethyl sulfoxide (DMSO) and were
administered immediately prior to experiment. Each subject was habituated in
testing cage for 30 min before scoring of locomotor activity over 24 h.