Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants

Article abstract of DOI:10.1016/j.bmcl.2005.03.083

To further explore the structure-activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a-b, 3d, 3f-h, 5b, and 7g were found to be h

Full text of DOI:10.1016/j.bmcl.2005.03.083

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2461–2465
Discovery of novel conformationally constrained tropane-based
biaryl and arylacetylene ligands as potent and selective
norepinephrine transporter inhibitors and potential antidepressants
Jia Zhou,a,* Thomas Klaß,b Kenneth M. Johnson,c
¨
Kelly M. Gibersonc and Alan P. Kozikowskia,b
aAcenta Discovery, Inc., 9030 S. Rita Road, Suite 300, Tucson, AZ 85747-9101, USA
bDepartment of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street,
Chicago, IL 60612-7230, USA
cDepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031, USA
Received 27 January 2005; revised 18 March 2005; accepted 21 March 2005
Available online 12 April 2005
Abstract—To further explore the structure–activity relationships of conformationally constrained tropanes, a number of new biaryl
and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a–b, 3d, 3f–h, 5b, and 7g were found to
be highly potent and selective or mixed norepinephrine transporter (NET) inhibitors with Ki values of 0.8–9.4 nM. Moreover, all of
these compounds display weak to extremely weak muscarinic receptor binding affinity, indicating that as potential antidepressants,
they may overcome certain side effects that are of concern with other antidepressants, which are thought to be mediated by their
anticholinergic properties.
ꢀ 2005 Elsevier Ltd. All rights reserved.
World-wide public health surveys point to an increased
global health burden for serious psychiatric disorders,
particularly depression, which has been referred to as
the Ôcommon coldÕ of mental illness. By 2020 it is ex-
pected that depression may be the second most serious
medical condition with respect to global disease bur-
den.1 For more than four decades, norepinephrine
(NE) has been postulated to play an important, possibly
primary, role in the pathophysiology and subsequent
treatment of major depressive disorder.2 To date, a
number of potent and selective or mixed norepinephrine
transporter (NET) inhibitors have been marketed as
antidepressants (Fig. 1). From 1960 to 1990, the tricyclic
antidepressants (TCAs) such as desipramine (Norpr-
aminꢁ), nortriptyline (Aventylꢁ, Pamelorꢁ), protripty-
line (Vivactilꢁ), and amoxapine (Asendinꢁ) were the
first-choice medications for major depressive disorder.3
TCAs are relatively selective NET and/or SERT inhibi-
tors, but they also possess a moderate affinity for a1-
adrenoceptors and muscarinic cholinergic receptors.
Muscarinic blockade and inhibition of norepinephrine
reuptake contribute to cardiac stimulation and tachycar-
dia, and these actions cause a number of troublesome
side effects. Cardiac arrhythmias that occur upon over-
dose are difficult to treat and can be life-threatening.
Other peripheral antimuscarinic side effects, including
dry mouth, urinary retention, and constipation, are also
prominent. These first-generation antidepressants
including the tetracyclic NET inhibitor maprotiline are
no longer widely used in the US due to the emergence
of newer, more effective drugs. However, TCA use re-
mains fairly common in other countries. A new genera-
tion of antidepressants resulted from the discovery of
selective serotonin reuptake inhibitors (SSRIs), which
have come to dominate the treatment of depression over
the last two decades. Although SSRIs such as fluoxetine
(Prozacꢁ) and paroxetine (Paxilꢁ) are very effective anti-
depressant drugs with substantially fewer side effects
than the older TCAs, they are not universally effective
and can also have bothersome side effects of their
own, such as anxiety, sleep disturbances, weight gain,
Keywords: NET inhibitors; Antidepressants; Muscarinic receptor affi-
nity; Conformationally constrained tropanes; Biaryl and arylacetylene
ligands.
*
Corresponding author. Tel.: +1 520 799 7304; fax: +1 520 799
7305; e-mail: jia.zhou@acentadiscovery.com
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.083

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J. Zhou et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2461–2465
better tolerated antidepressants. Previously, we reported
two classes of molecules, namely conformationally con-
strained tropanes and piperidine-based nocaine/modafi-
nil hybrid ligands, as potent NET inhibitors.11–14 To
further explore the structure–activity relationships of
conformationally constrained tropanes, a number of
new biaryl and arylacetylene analogs were designed,
synthesized and their monoamine transporter activity
tested. To gain insights into their potential applications
for the treatment of depression, we have also investi-
gated the binding affinity of these compounds at the
muscarinic receptor in continuation of our previous
work, and the results will be discussed herein.
N
N
H
N
H
N
H
Desipramine
Nortriptyline
Protriptyline
NH
CH2(CH2)2NHCH3
N
N
Cl
O
Amoxapine
Maprotiline
OMe
In the course of our extensive synthetic studies in the
field of conformationally constrained tricyclic tropane
compounds, we have developed a satisfactory synthesis
for the key intermediate, (Z)-vinylstannane 1.11 Scheme
1 outlines our synthetic approach to the newly designed
biaryl and arylacetylene analogs. The key intermediates
2 and 4 were prepared in moderate yields by the Stille
coupling of the vinylstannane 1 with 1,4-diiodobenzene
or 2,5-diiodothiophene, utilizing previously reported
procedures.11,12 The subsequent Suzuki coupling of the
iodides 2 and 4 with substituted phenylboronic acids
or heteroarylboronic acids in the presence of Pd(OAc)2
as the catalyst provided the desired biaryl analogs 3a–i
and 5a–b in moderate to high yields. Our synthesis of
the arylacetylene ligands makes use of the Sonogashira
coupling reaction. Thus, the vinyl iodide 6, which was
obtained by iodination of 1, upon coupling with aryl-
acetylenes generated the analogs 7a–b and 7i. Due to
the limited availability of arylacetylenes, the remaining
compounds 7c–h were synthesized in a stepwise manner
by two consecutive Sonogashira coupling reactions via
key intermediate 8, utilizing readily available aryl iod-
ides or bromides for the introduction of the aryl or het-
eroaryl moiety. In this reaction, the coupling with
iodides for 7c–e and 7h gave much better yields than
that with bromides for 7f–g. The structures and purity
of all synthesized compounds were confirmed by 1H
and 13C NMR, EI-MS, and by HPLC or elemental
analysis.15
OEt
O
O
H
HN
Me
NH
O
(R)-Nisoxetine
Reboxetine
OMe
O
N
H
H
O
O
CH3
N
NHMe
Cl
Bupropion
S
Venlafaxine
Duloxetine
Figure 1. Selective or mixed NET inhibitors used as antidepressants.
sexual dysfunction, and gastrointestinal disturbances.4
The success and challenges of the SSRIs rekindled inter-
est in the development of selective NET inhibitors as
potential antidepressants. Pharmacologically and chemi-
cally unrelated to TCAs or SSRIs, reboxetine (Edro-
naxꢁ) is the first truly selective NET inhibitor that is
currently being marketed as an antidepressant in over
50 countries including Europe. The selectivity of reboxe-
tine for the NET and its benign side effect profile cause
the drug to be well tolerated.5,6 Some dual transporter
inhibitors also display a unique clinical profile. Bupro-
pion (Wellbutrinꢁ) for example, a dual NET/DAT li-
gand, has demonstrated efficacy comparable to that of
other antidepressants and without the side effects of
SSRIs.7 As a dual NET/SERT inhibitor, venlafaxine
(Effexorꢁ) represents a new class of antidepressants
and has a higher rate of efficacy and a lower dropout
rate when compared to TCAs and SSRIs.8 Another dual
NET/SERT inhibitor, duloxetine (Cymbaltaꢁ), FDA-
approved in 2004, is a well-tolerated antidepressant
and even more effective than venlafaxine.9
All compounds were tested as the free base for their abil-
ity to inhibit high-affinity reuptake of DA, 5-HT, and
NE into nerve endings (synaptosomes) prepared from
brain regions enriched in transporters for these biogenic
amine neurotransmitters.16 The effect of candidate com-
pounds in antagonizing biogenic amine high-affinity up-
take was determined using a method similar to that
previously employed for [3H]DA uptake.17 Rat striatum,
midbrain, and parietal/occipital cortex were dissected
and used as a source of DAT, SERT, and NET, respec-
tively. The Cheng–Prusoff equation for classic, competi-
tive inhibition was used for calculating Ki from IC50
values in uptake experiments. The Km values used were
67 nM for [3H]DA, 53 nM for [3H]5-HT, and 54 nM for
[3H]NE. [3H]Quinuclidinyl benzilate (QNB) is a musca-
rinic antagonist that has a high affinity for all muscarinic
receptor subtypes. It was used to label muscarinic recep-
tors in rat cortex, and displacement of [3H]QNB from
these sites by NET-selective compounds was used to
Recently, the FDA issued warnings to the public about
an increased risk of suicidal thoughts and behavior
(ÔsuicidalityÕ) in children and adolescents being treated
with antidepressant medications.10 Such side effect issues
have prompted a new search for safer, faster-acting and

J. Zhou et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2461–2465
2463
R
a
c
e
3a-e
b
d
I
R
2-OMe 3-OMe 2-F 3-F 4-F
SnBu3
g
3f-i
f
h
i
N
N
N
a
c
b
E
E
E
R
3-CF3 3,4-F2 3,5-F2 4-SMe
E = COOMe
2
3a-i
1
Ar
I
S
S
d
e
N
N
E
E = COOMe
E
4
5a-b
Ar
5a-b, 7a-c
5a
5b
7a
7b
7c
I
SMe
F
F
S
N
N
Ar
E
f
E
7a-i
6
7g
7d-i
7d
7e
Me
7f
7h
7i
g
TMS
h
F
F
S
F
F
S
Ar
F
N
F
F
E
E = COOMe
8
Scheme 1. Synthesis of new conformationally constrained tropanes as NET inhibitors. Reagents and conditions: (a) 1,4-diiodobenzene, Ph3As,
Pd2(dba)3, CuI, DMF, 50 ꢂC, 57%; (b) arylboronic acids, Pd(OAc)2, K2CO3, H2O/THF, 70–80 ꢂC, 41–78%; (c) 2,5-diiodothiophene, Ph3As,
Pd2(dba)3, CuI, DMF, 50 ꢂC, 55%; (d) aryl- or heteroarylboronic acids, Pd(OAc)2, K2CO3, H2O/THF, 70–80 ꢂC, 40%; (e) I2, CH2Cl2, rt, 88%; (f)
arylacetylenes (for 7a–b and 7i), PdCl2(PPh3)2, CuI, Et3N, DME, 80 ꢂC, 62–80%; (g) (trimethylsilyl)acetylene, PdCl2(PPh3)2, CuI, Et3N, DME,
80 ꢂC, 17 h, 70%; (h) aryl iodides (for 7c–e and 7h) or aryl bromides (for 7f–g), PdCl2(PPh3)2, CuI, Et3N, TBAF, DME, 80 ꢂC, 17–80%.
screen for muscarinic receptor affinity as previously pub-
lished.18,19 The DA, 5-HT, and NE uptake data and
selectivity profiles (based on the Ki values) as well as
the muscarinic receptor affinity data of all compounds
are listed in Table 1. For comparison purposes, the inhi-
bition data of reuptake at monoamine transporters for
the known compound 5a12 from our previous paper
are also included. All data are mean values SEM from
two to four independent experiments, each consisting of
six concentrations of test compound in triplicate. The
concentrations chosen for testing were based on a preli-
minary screening designed to approximate the IC50.
In the series of conformationally constrained tropane li-
gands, modifications of the substituents on the outer
phenyl ring led to a significant improvement of potency
and selectivity at the NET. Ligands 3a with 2-methoxy,
3b with 3-methoxy, 3d with 3-fluoro, 3f with 3-trifluo-
romethyl, 3g with 3,4-difluoro, and 3h with 3,5-difluoro
substituents display a remarkable potency from nano-
molar to subnanomolar at the NET, and all of these po-
tent NET ligands exhibit very low binding affinity at the
muscarinic receptor with Ki values higher than 2830 nM.
Particularly, both ligands 3a and 3g, like (R)-nisoxe-
tine,20 display not only an excellent potency with Ki val-
ues of 6.5 and 0.8 nM at the NET, but also more than
100-fold selectivity versus both the SERT and the
DAT. Ligand 3h is a potent and dual NET/SERT inhib-
itor with Ki values around 1 nM having a selectivity pro-
file like duloxetine21,22 and venlafaxine,23,24 and it
displays a very weak muscarinic receptor binding affinity
with a Ki value of 2830 nM. The bithienyl tropane li-
gand 5b is a potent NET inhibitor with a Ki value of
The data shown in Table 1 demonstrate that some of the
newly designed biaryl and arylacetylene analogs such as
3a–b, 3d, 3f–h, 5b, and 7g exhibit a very high potency at
the NET. On the other hand, all compounds, including
those that are remarkably potent NET inhibitors, dis-
play weak to extremely weak (Ki >10,000 nM) binding
affinity at the muscarinic receptor.

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J. Zhou et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2461–2465
Table 1. Binding affinity at the muscarinic receptor and inhibition of reuptake at monoamine transporters (Ki SEM (nM))a
Compound
[3H]QNB binding
Ki (nM)
[3H]DA uptake
Ki (nM)
[3H]5-HT uptake
Ki (nM)
[3H]NE uptake
Ki (nM)
Uptake ratio (based on Ki)
5-HT/DA
NE/DA
NE/5-HT
Desipramineb
—
>10,000
>10,000
163c
1340
7.36
—
—
—
3a
3b
3c
3d
3e
3f
787 234
114 40
3400 545
646 29
7
6.5 2.1
9.4 1.1
393 102
5.0 2.3
1.70
3.04
0.14
0.21
8.62
2.10
2.78
0.005
1.02
2.01
0.28
N/d
N/d
N/d
0.02
0.13
N/d
N/d
N/d
N/d
0.008
0.08
0.12
0.01
0.33
0.02
0.007
0.005
0.06
0.16
0.05
N/d
N/d
N/d
0.03
0.007
N/d
N/d
N/d
N/d
0.004
4060 1240
>10,000
>10,000
346 66
466 44
138 23
0.03
0.84
0.04
0.04
0.007
0.002
1.09
0.06
0.08
0.18
1060 279
7060 2377
3400 809
2830 779
>10,000
161
556 19
106
9
1390 56
1170 425
295 36
53
2
8.8 0.5
0.8 0.2
1.3 0.3
3g
3h
3i
6
228 28
1050 81
1650 47
1.2 0.7
1080 96
3320 525
62
3
5ad
5b
7a
7b
7c
7d
7e
7f
>10,000
273 37
5.9 0.9
2140 446
11,900 421
15,100 2580
13,500 791
7090 2010
>10,000
114
>10,000
>10,000
>10,000
4
32
207 20
2
>10,000
104
N/d
17
317
69
3
3
4
9
9
6.20
6.66
1.59
0.06
7.99
0.17
2110 41
110 21
3150 1150
7070 1794
914
52
1
>10,000
>10,000
>10,000
215 60
32
1720 262
5.3 0.7
1570 503
7g
7h
7i
>10,000
>10,000
>10,000
6
13,900 799
2740 366
142 32
86 17
11.8
0.25
22
3
a Ki values are means SEM from two to four independent experiments, each consisting of six drug concentrations (in triplicate) that were selected
on the basis of preliminary screening experiments to bracket the approximate IC50 value.
b Data taken from Ref. 20.
c Data for cloned human receptors.
d Inhibition data of reuptake at monoamine transporters were taken from Ref. 12.
5.9 nM, and exhibits a fairly low binding affinity at the
muscarinic receptor with a Ki value of 2140 nM. Among
all compounds tested, ligand 3e has the highest
[3H]QNB binding affinity with a Ki value of 1060 nM,
but it merely shows a moderate potency at the NET with
a Ki value of 53 nM. The arylacetylene analogs 7a–i
were designed based on the structures of our biaryl li-
gands by the replacement of inner phenyl ring with a tri-
ple bond as an aromatic ring bioisostere. Generally, they
display a reduced potency particularly at the DAT and
NET. Interestingly, compound 7b exhibits a fairly good
potency at the SERT with a Ki value of 17 nM. Com-
pound 7g is a potent NET inhibitor with a Ki value of
5.3 nM and a selectivity profile resembling that of desi-
pramine,20 however, it has substantially no binding
affinity at the muscarinic receptor (Ki >10,000 nM).
Acknowledgements
This work was supported by an STTR grant from NIH/
NIMH (1R41MH070083-01) and grants from NIH/
NIDA (DA10458, DA11548). The authors also thank
Dr. Werner Tueckmantel and Mr. Hans F. Roth of
Acenta Discovery, Inc. for helpful discussions.
References and notes
1. The Global Burden of Disease; Murray, C. J. L., Lopez, A.
D., Eds.; Harvard University Press: Cambridge, MA,
1996.
2. (a) Ressler, K. J.; Nemeroff, C. B. Biol. Psychiat. 1999, 46,
1219; (b) Blier, P. J. Psychiat. Neurosci. 2001, 26(Suppl.),
S1; (c) Van Moffaert, M.; Dierick, M. CNS Drugs 1999,
12, 293; (d) Zhou, J. Drugs Future 2004, 29, 1235, and
references cited therein.
In conclusion, a number of new biaryl and arylacetylene
analogs were designed, synthesized and some of them
such as 3a–b, 3d, 3f–h, 5b, and 7g were found to be
highly potent and selective or mixed NET inhibitors.
Moreover, the binding affinities of these tropane ligands
at the muscarinic receptor have also been investigated.
The data demonstrate that there is no direct correlation
between the muscarinic receptor affinity and the trans-
porter activities of these ligands. It was found that this
class of selective or mixed NET inhibitors display weak
to extremely weak muscarinic receptor binding affinity,
indicating that as potential antidepressants they may
overcome certain side effects of existing antidepressant
drugs that are thought to be mediated by their anticho-
linergic properties. Behavioral assessment of some of
these ligands is currently underway.
3. Kando, J. C.; Wells, B. G.; Hayes, P. E. In Drug Facts and
Comparisons; Kastrup, E. K., Ed.; Facts and Compari-
sons: Louis, MO, 2004.
4. Stahl, S. M. J. Clin. Psychiat. 1998, 59(Suppl. 4), 5.
5. Wong, E. H. F.; Sonders, M. S.; Amara, S. G.; Tinholt, P.
M.; Piercey, M. F. P.; Hoffmann, W. P.; Hyslop, D. K.;
Franklin, S.; Porsolt, R. D.; Bonsignori, A.; Carfagna, N.;
McArthur, R. A. Biol. Psychiat. 2000, 47, 818.
6. Page, M. E. CNS Drug Rev. 2003, 9, 327.
7. Stahl, S. M.; Pradko, J. F.; Haight, B. R.; Modell, J. G.;
Rockett, C. B.; Learned-Coughlin, S. J. Clin. Psychiat.
2004, 6, 159.
8. Einarson, T. R.; Addis, A.; Mittmann, N.; Iskedjian, M.
Can. J. Clin. Pharmacol. 1998, 5, 205.
9. Anttila, S.; Leinonen, E. Curr. Opin. Investig. Drugs 2002,
3, 1217.

J. Zhou et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2461–2465
2465
2
52.5, 54.3, 57.1, 86.3, 93.6, 101.3, 118.0 (d, JCCF
10. For details, see the web site: http://www.antidepressants-
facts.com/children.htm.
11. Zhou, J.; Zhang, A.; Kla¨ß, T.; Johnson, K. M.; Wang, C.
Z.; Ye, Y. P.; Kozikowski, A. P. J. Med. Chem. 2003, 46,
1997.
12. Zhou, J.; Kla¨ß, T.; Zhang, A.; Johnson, K. M.; Wang, C.
Z.; Ye, Y. P.; Kozikowski, A. P. Bioorg. Med. Chem. Lett.
2003, 13, 3565.
13. Kla¨ß, T.; Zhou, J.; Zhang, A.; Petukhov, P. A.; Johnson,
K. M.; Wang, C. Z.; Ye, Y. P.; Kozikowski, A. P.
Abstracts of Papers, 226th National Meeting of the
American Chemical Society, New York, September 7–11,
2003; American Chemical Society: Washington, DC, 2003.
14. Zhou, J.; He, R.; Johnson, K. M.; Ye, Y.; Kozikowski, A.
P. J. Med. Chem. 2004, 47, 5821.
=
=
=
3
23.7 Hz), 123.1 (d, JCCCF = 9.6 Hz), 125.7 (d, JCCF
2
4
17.2 Hz), 127.4 (d, JCCCCF = 3.3 Hz), 131.8 (d, JCCCF
3
5.8 Hz), 155.2, 161.2 (d, JCF = 245.1 Hz), 174.4; EI-MS
m/z (%) 339 (M+, 3), 280 (3), 183 (2), 139 (3), 137 (5), 99
(7), 86 (60), 84 (100), 49 (41), 47 (43), 44 (15), 41 (20).
HPLC analysis conditions are same as described above;
Retention time tR = 21.0 min; purity (by peak area) 98.5%.
16. Slusher, B. S.; Tiffany, C. W.; Olkowski, J. L.; Jackson,
P. F. Drug Alcohol Depend. 1997, 48, 43.
17. Wang, S.; Sakamuri, S.; Enyedy, I. J.; Kozikowski, A. P.;
Deschaux, O.; Bandyopadhyay, B. C.; Tella, S. R.;
Zaman, W. A.; Johnson, K. M. J. Med. Chem. 2000, 43,
351.
18. Johnson, K. M.; Hillman, G. R. J. Pharm. Pharmacol.
1982, 34, 462.
15. Spectra data of the representative compounds:
(1S,3S,6R,10S)-(Z)-9-[4-(2-methoxyphenyl)benzylidene]-
7-azatricyclo[4.3.1.03,7]decane-10-carboxylic acid methyl
19. In this assay, rat brain cortical membranes (300 mg of
protein) are prepared in a standard fashion and incubated
at 37 ꢂC in 50 mM sodium and potassium phosphate
buffer in the presence of 200 pM [3H]QNB and vary-
ing concentrations of test compound for 60 min (time to
equilibrium). Membrane-bound [3H]QNB is separated by
rapid filtration on glass fiber filters and washed twice with
5 mL of buffer. Filters are counted by LS spectrometry.
Specific binding is calculated by subtracting binding in the
presence of 10 lM atropine sulfate, and the IC50 is
calculated by fitting to a four parameter logistic equation
for a sigmoidal fit. The data are converted to Ki by the use of
25
ester (3a): ½aꢀD +43.3ꢂ (c 0.09, CHCl3); 1H NMR
(250 MHz, CDCl3) d 1.42–1.58 (m, 3H), 2.02–2.30 (m,
3H), 2.43 (t, J = 3.0 Hz, 1H), 2.73 (dd, J = 3.0 and 5.4 Hz,
1H), 3.25–3.38 (m, 1H), 3.66 (s, 3H), 3.72–3.88 (m, 1H),
3.81 (s, 3H), 3.98 and 4.10 (ABq, J = 18.6 Hz, both d with
J = 2.4 Hz, 2H), 6.17 (t, J = 2.7 Hz, 1H), 6.94–7.06 (m,
2H), 7.20–7.35 (m, 4H), 7.50 (d, J = 8.5 Hz, 2H); 13C
NMR (62.9 MHz, CDCl3) d 31.9, 32.6, 36.5, 37.3, 48.3,
51.9, 52.3, 53.8, 55.5, 56.2, 111.2, 120.8, 122.0, 128.0,
128.6, 129.5, 130.3, 130.7, 136.0, 136.4, 140.2, 156.5, 174.2;
EI-MS m/z (%) 389 (M+, 0.2), 212 (0.1), 119 (2), 99 (13), 86
(60), 84 (100), 49 (39), 47 (49), 41 (18). HPLC analysis
conditions: Supelco Discovery C18 column with guard
column, 250 · 3 mm, 5 lm particle size; solvent: A = 0.1%
CF3COOH (TFA) in water and B = 0.1% TFA in
CH3CN; gradient: from 10% to 80% B in 20 min, then
80% B for an additional 10 min; UV detection at 270 nm;
Retention time tR = 22.1 min; purity (by peak area) 97.0%.
(1S,3S,6R,10S)-(Z)-9-[3-(3-Fluoro-4-methylphenyl)-prop-
2-ynylidene]-7-azatricyclo[4.3.1.03,7]decane-10-carboxylic
the Cheng–Prusoff equation assuming
relationship.
a competitive
20. Detailed data can be found in the NIMH/PDSP Ki
Database via the web site http://kidb.bioc.cwru.edu/
pdsp.php.
21. Boot, J. R.; Brace, G.; Delatour, C. L.; Dezutter, N.;
Fairhurst, J.; Findlay, J.; Gallagher, P. T.; Hoes, I.;
Mahadevan, S.; Mitchell, S. N.; Rathmell, R. E.; Rich-
ards, S. J.; Simmonds, R. G.; Wallace, L.; Whatton, M. A.
Bioorg. Med. Chem. Lett. 2004, 14, 5395.
22. Bymaster, F. P.; Beedle, E. E.; Findlay, J.; Gallagher, P.
T.; Krushinski, J. H.; Mitchell, S.; Robertson, D. W.;
Thompson, D. C.; Wallace, L.; Wong, D. T. Bioorg. Med.
Chem. Lett. 2003, 13, 4477.
23. Dubovsky, S. L. J. Clin. Psychiat. 1994, 55(Suppl.),
34.
25
acid methyl ester (7e): ½aꢀD +145.1ꢂ (c 0.06, CHCl3);
1H NMR (250 MHz, CDCl3) d 1.42–1.60 (m, 3H), 1.92–
2.06 (m, 1H), 2.10–2.30 (m, 2H), 2.26 (d, JHCCCF
4
= 2.0 Hz, 3H), 2.38 (t, J = 3.0 Hz, 1H), 2.72 (dd, J = 3.3
and 5.6 Hz, 1H), 3.26–3.32 (m, 1H), 3.68 (s, 3H), 3.70–3.78
(m, 1H), 3.83 (t, J = 3.0 Hz, 2H), 5.44 (t, J = 2.8 Hz, 1H),
7.01–7.15 (m, 3H); 13C NMR (62.9 MHz, CDCl3) d 15.0
24. Brunello, N.; Racagni, G. Human Psychopharmacol. 1998,
13, S13.
3
(d, JCCCF = 3.4 Hz), 32.6, 33.0, 35.9, 36.6, 48.5, 52.3,