Discovery of N1-(6-Chloroimidazo[2,1-b][1,3]-thiazole-5- sulfonyl)tryptamine as a potent, selective, and orally active 5-HT6 receptor agonist

Article abstract of DOI:10.1021/jm070521y

N₁-Arylsulfonyltryptamines have been identified as 5-HT ₆ receptor ligands. In particular, N₁(6-chloroimidazo[2,1- b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT₆ K

Full text of DOI:10.1021/jm070521y

© Copyright 2007 by the American Chemical Society
Volume 50, Number 23
November 15, 2007
Letters
Discovery of N1-(6-Chloroimidazo[2,1-b][1,3]-
thiazole-5-sulfonyl)tryptamine as a Potent,
Selective, and Orally Active 5-HT6 Receptor
Agonist
Derek C. Cole,*,† Joseph R. Stock,† William J. Lennox,†
Ronald C. Bernotas,‡ John W. Ellingboe,† Steve Boikess,§
Joseph Coupet,§ Deborah L. Smith,§ Louis Leung,#
Guo-Ming Zhang,§ Xidong Feng,† Michael F. Kelly,†
Rocco Galante,† Pingzhong Huang,† Lee A. Dawson,§
Karen Marquis,§ Sharon Rosenzweig-Lipson,§
Chad E. Beyer,§ and Lee E. Schechter§
Chemical and Screening Sciences, Wyeth Research,
401 N. Middletown Road, Pearl RiVer, New York 10965, Chemical
& Screening Sciences, Wyeth Research, 500 Arcola Road,
CollegeVille, PennsylVania 19426, DiscoVery Neurosciences, Wyeth
Research, Princeton, New Jersey 08852, and Drug Safety &
Metabolism, Wyeth Research, 500 Arcola Road,
Figure 1. Structures of 5-HT6 receptor antagonists (1, 2) and agonists
(3-5).
drugs1,3 have promoted much interest in 5-HT6 receptors as
attractive targets for antipsychotic therapeutic agents, with the
possibility of relatively few noncentrally mediated peripheral
side effects.6
CollegeVille, PennsylVania 19426
ReceiVed May 3, 2007
Much research has focused on the identification of selective
5-HT6 receptor antagonists, which have been reported to play
a significant role in memory formation under normal and
dysfunctional conditions. Meneses et al. have shown that the
5-HT6 receptor antagonist Ro-04-67907 (1, Figure 1) improved
learning consolidation in an autoshaping task and that SB-
2710468 (2) improved memory retention in the water maze and
produced a significant performance improvement in aged rats,
and a series of analogues based on 1 reversed scopolamine-
induced retention deficit in a passive avoidance learning test.9
5-HT6 antisense oligonucleotides facilitate a reduction in food
intake and body weight in rats, an effect also seen with the
antagonists 1 and 2.10
In contrast to 5-HT6 antagonists, the identification of selective
5-HT6 agonists has proven much more difficult. Tsai et al.
reported the 5-HT6 receptor full agonist 2-ethyl-5-methoxy-N,N-
dimethyltryptamine (EMDT, 3), which binds with high affinity
at 5-HT6 receptors (Ki ) 16 nM).11 However, 3 is only 10- to
30-fold selective over 5-HT1A, 5-HT1D, and 5-HT7 receptors.
Mattsson et al. reported that 5-chloro-2-methyl-3-(1,2,3,6-
tetrahydropyridin-4-yl)-1H-indole (4) is a high affinity (5-HT6
IC50 ) 7.4 nM) full agonist (EC50 ) 1.0 nM).12 But 4 also
Abstract: N1-Arylsulfonyltryptamines have been identified as 5-HT6
receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-
5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-
HT6 Ki ) 2 nM, EC50 ) 6.5 nM, Emax ) 95.5%). Compound 11q is
selective in a panel of over 40 receptors and ion channels, has good
pharmacokinetic profile, has been shown to increase GABA levels in
the rat frontal cortex, and is active in the schedule-induced polydipsia
model for obsessive compulsive disorders.
The 5-hydroxytryptamine-6 (5-HT6) receptor was identified
in the 1990s1-3 and was shown to belong to a group of 5-HT
receptors, including 5-HT4 and 5-HT7 that stimulate adenylate
cyclase activity.4 The 5-HT6 receptor has no known functional
splice variants, is expressed almost exclusively in the central
nervous system (CNS), and is localized in the striatal, limbic,
and cortical regions of the rat brain.5 Their CNS localization
and high affinity for many antipsychotic and antidepressants
* To whom correspondence should be addressed. Phone: 845-602-4619.
Fax: 845-602-5561. E-mail:coledc@wyeth.com.
† Wyeth Research, NY.
‡ Chemical & Screening Sciences, Wyeth Research, PA.
§ Wyeth Research, NJ.
# Drug Safety & Metabolism, Wyeth Research, PA.
10.1021/jm070521y CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/19/2007

5536 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Letters
Scheme 1a
a (a) (Boc)2O, K2CO3, acetone, water (96%); (b) ArSO2Cl, Aliquat 336,
50% aqueous NaOH, DCM (60%); (c) 4 N HCl/dioxane, THF (95%).
and amidines (8b) as replacements. The N1-arylsulfonyl-
tryptamine intermediates (11) were assayed and found to have
high affinity for 5-HT6 receptors and in some cases potent
agonist activity. N1-Aryltryptamine derivatives have previously
been reported as high-affininty 5-HT6 receptor ligands, for
example, the antagonist 9a,11 partial agonist 9b,14 and the
“flipped” tryptamine derivative 10.15
Figure 2. N1-Arylsulfonyltryptamine type 5-HT6 ligands.
possesses significant affinity for other 5-HT receptors, in
particular 5-HT3 (IC50 ) 34 nM). We have described 5-aryl-
sulfonamidoindoles in which the (R)-isomers generally act as
full agonists, for example, 5 (5-HT6 Ki ) 1 nM, EC50 ) 1.1
nM).13 Unfortunately, 5 also suffers from modest selectivity (15-
and 16-fold vs 5-HT1B and 5-HT1D, respectively). Thus, the
usefulness of these compounds as tools to probe the pharmacol-
ogy of the 5-HT6 receptors is somewhat limited by their modest
selectivity.
Herein, we report the discovery of N1-(6-chloroimidazo[2,1-
b][1,3]thiazole-5-sulfonyl)tryptamine (11q, WAY-181187, SAX-
187), a novel 5-HT6 agonist with >50-fold selectivity against
serotonin and other receptors. The synthesis, structure-activity
relationships, and physiochemical, pharmacokinetic, and in vivo
profiles are the subjects of this communication.
Our 5-HT6 receptor discovery efforts began with a focused
screen of the biogenic amine-type compounds in Wyeth’s
compound collection. Compounds were tested for displacement
of [3H]LSD from 5-HT6 receptors stabily expressed in cultured
HeLa cells and led to the identification of 5-bromoindole
aminoguanidine (6: 5-HT6 Ki ) 25 nM, Figure 2). Synthesis
of analogues around this hit demonstrated that N1-arylsulfonyl
substitution on the indole gave compounds (e.g., 7) with
enhanced 5-HT6 receptor binding affinity and selectivity over
5-HT7. However, the aminoguanidine imine bond is acid-labile,
so we sought other basic moieties such as the guanidines (8a)
The N1-arylsulfonyl tryptamine array was readily prepared
by Boc protection of the tryptamine primary amine, base-
mediated sulfonylation of the indole nitrogen, and removal of
the protecting group (Scheme 1). N1-Phenylsulfonyltryptamine
(11a) and substituted phenylsulfonyltryptamines (11b-k) are
high-affinity 5-HT6 receptor ligands (5-HT6 Ki ) 1-30 nM)
and many behave as partial or full agonists with modest potency
(EC50 ) 73-191 nM) (Table 1). The 4-aminophenyl analogue
11j has the highest affinity (5-HT6 Ki ) 1 nM), consistent with
other series in which the p-amino substitution gave the highest
5-HT6 receptor affinity.13 Interestingly, the 3,4-dimethoxyphen-
ylsulfonyl (11l, Ki ) 7 nM, IC50 ) 17.5 nM) and 2-amino-3-
methyl-5-thiazolylsulfonyl analogues (11p, Ki ) 10 nM, IC50
) 9.6 nM) failed to show any agonist activity but instead
behaved as antagonists. The mono- and bishalothiophenesulfonyl
derivatives (11m-o, Ki ) 6-31 nM, EC50 ) 54-181 nM) had
high affinity with modest agonist activity. Most intriguing was
6-chloroimidazo[2,1-b][1,3]thiazolesulfonyl analogue 11q, which
was a very high affinity, potent full agonist (5-HT6 Ki ) 2 nM,
EC50 ) 6.5 nM).
When 11q was examined for selectivity against a panel of
serotonergic receptors, significant affinity was only seen for the
5-HT2C (agonist) receptor binding site, but 11q still showed
greater than 50-fold selectivity (Table 2). In a panel of 31 other
receptors and ion channels, 11q showed less than 50% displace-
ment at 100 nM at the R-adrenergic (1A, 1B, 2A-C), â-ad-
Table 1. 5-HT6 Receptor Binding and Functional Activity
compd
Ar
Ki (nM)a,d
EC50 (nM)b,d
Emax (%)b,d
IC50 (nM)c,d
Imax (%)c,d
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
11p
11q
Ph
2-Br-Ph
2-I-Ph
3-Cl-Ph
4-F-Ph
4-Cl-Ph
4-I-Ph
4-Me-Ph
4-MeO-Ph
4-NH2-Ph
3,4-di-Cl-Ph
3,4-di-MeO-Ph
5-Cl-2-thienyl
5-Br-thienyl
4,5-di-Cl-2-thienyl
2-NH2-3-Me-5-thiazolyl
6-Cl-imidazothiazole
10 ( 1
11 ( 1
16 ( 1
6 ( 1
73 ( 39
92 ( 8
148 ( 28
97.5 ( 2.5
108.5 ( 2.5
174 ( 8
100 ( 0
93.5 ( 0.3
87.5 ( 1.1
73 ( 8
21 ( 2
10 ( 1
14 ( 1
8 ( 1
191 ( 8
47 ( 5
1 ( 0
91 ( 15
30 ( 3
7 ( 1
17.5 ( 4.6
9.6 ( 1.0
80.5 ( 0.4
83 ( 0
6 ( 1
7 ( 1
181 ( 23
54 ( 12
100 ( 0
72 ( 4
31 ( 2
10 ( 1
2 ( 0
6.5 ( 0.5
95.5 ( 4.5
a Displacement of [3H]LSD binding to cloned h5-HT6 receptors stably expressed in HeLa cells. b Agonism of cAMP production in HeLa cells stably
transfected with human 5-HT6 receptors. c Antagonism of 5-HT stimulated cAMP production in HeLa cells stably transfected with human 5-HT6 receptors.
d All values are the mean ( SD (n ) 3).

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5537
Table 4. Pharmacokinetic Profile of 11q in Rats and Dogs
Table 2. Binding Affinity of 11q at Other 5-HT Receptorsa
Ki
(nM)
inhibition at
100 nM (%)
inhibition at
1 µM (%)
1 mg/kg
iva,e
(rat)
10 mg/kg
oralb,e
(rat)
1 mg/kg
ivc,e
(dog)
5 mg/kg
orald,e
(dog)
receptor
5-HT1B
5-HT1D
5-HT1F
5-HT2A (antagonist)
5-HT2A (agonist)
5-HT2B
5-HT2C (antagonist)
5-HT2C (agonist)
5-HT3
36
21
40
25
49
AUC
0.14 ( 0.03
0.19 ( 0.05
0.52 ( 0.15 1.43 ( 0.37
0.13 ( 0.05
(µg h mL-1
Cmax
)
0.049 ( 0.007
(µg mL-1
)
458
124
t
t
max (h)
1/2 (h)
1.7 ( 0.6
3.1 ( 0.0
2.3 ( 1.5
6.6 ( 0.7
51
5.4 ( 1.0
7.4 ( 1.4
2.9 ( 0.3
1.8 ( 0.5
Cl
<50
<50
<50
(L h-1 kg-1
)
5-HT4
5-HT5
5-HT7
Vss
24.0 ( 4.0
7.9 ( 1.5
(L kg-1
)
679
F (%)
23
55
a Receptors were all human clones stably expressed in CHO cells.
a In 2% Tween-80 at 1 mL/kg. b In 2% Tween/0.5% methyl cellulose at
10 mL/kg. c In saline at 1 mL/kg. d In 2% Tween/0.5% MC at 1 mL/kg.
e Results are the mean ( SD of n ) 3.
Radioligands were as follows. 5-HT1A
: ,
8-hydroxy[3H]DPAT. 5-HT1B
5-HT1D, 5-HT1F, 5-HT2C: [3H]-5-HT. 5-HT2A: [125I]DOI. 5-HT6, 5-HT7:
[3H]LSD. Ki values were determined in triplicate.
Table 3. Physiochemical and Metabolic Profile for 11q
assay type
aqueous solubility (mg/mL)a
at pH 3-6
>10
at pH 8
0.24
permeability (cm/s)b
PAMPA18
13.6 × 10-6
1.2 × 10-6
BBB17
cytochrome P450 inhibition, IC50 (µM)a
1A2
2A6
149
41
2C19
2C8
2C9
2D6
112
>500
>500
196
33
Figure 3. Mean plasma and brain concentration of 11q after a single
ip (3 mg/kg) or oral (100 mg/kg) dose in rats.
3A4
microsomal stability, t1/2 (min)a
mouse
rat
dog
monkey
human
>60
8
26
6.4
>60
the hepatic blood flow (∼3.3 L h-1 kg-1), suggesting other
clearance pathways in addition to hepatic metabolic clearance.
A 10 mg/kg oral dose was rapidly absorbed, had an elimination
half-life (t1/2) of 3.1 h, and an oral bioavailabilty (F) of 23%.
The low oral bioavailability of 11q in rats is consistent with its
high metabolic instability in rat liver microsomal incubations.
The oral bioavailablility in rats decreased with increasing dose
above 100 mg/kg (data not shown), suggesting that oral
absorption might have become limiting. In dogs the plasma
clearance was high and approximately equal to hepatic blood
flow (1.8 L h-1 kg-1). The volume of distribution (Vss) was
large (7.9 L/kg) and with a half-life (t1/2) of 6.6 h and an oral
bioavailability (F) of 55%. The higher oral bioavailability of
11q in dogs also is consistent with its higher microsomal
stability in this species. In contrast to rats, the oral bioavailability
in dogs increased with increasing dose above 5 mg/kg (data
not shown), suggesting saturation of hepatic first-pass or
metabolic clearance. The brain and plasma ratio (0.1-0.7) of
11q after a single 3 mg/kg ip or 100 mg/kg oral dose in rats
indicates moderate blood-brain barrier penetration (Figure 3).
The in vivo activity of 11q was demonstrated in the schedule-
induced polydipsia (SIP) model in rats, a model, which may be
predictive of efficacy in obsessive compulsive disorder (OCD).19
Selective serotonin reuptake inhibitors (SSRIs) have been shown
to decrease adjunctive drinking under SIP conditions but have
a delayed onset of action cosistent with clinical findings using
SSRIs to treat OCD.19 In comparison, 11q decreased adjunctive
drinking in a dose-related fashion following acute ip and oral
administration. The high oral dose required for efficacy may
be due the instability in rat liver microsomal incubations.
Importantly, control studies demonstrated that 11q did not
a Determined in duplicate with standard error of <20%. b Determined
in triplicate with standard error of <20%.
renergic (1, 2), adenosine (1, 2), dopamine (D1-4), histamine
(1-3), muscarinic (1-5), GABA A (agonist and benzodiazepine
binding), glutamate (AMPA, kainate, NMDA, glycine), puri-
nergic P2Y, and σ (1, 2) receptors. Greater than 50% displace-
ment was only observed at the highest concentration of 10 µM
in six receptors (D1, R2A, R2B, â1, â2, and σ2).
Selective 5-HT6 receptor agonist 11q was further evaluated
for its physiochemical profile and metabolic stability in a series
of in vitro assays (Table 3). With a pKa of 10.2, 11q had
solubility of >10 mg/mL at pH 3-6, decreasing above pH 7.4.
Compound 11q is predicted to be membrane and blood-brain
barrier (BBB) permeable based on in vitro assays.16-18 The
effect of 11q on cytochrome P450 (CYP) enzyme catalytic
activity was determined in human liver microsomes in which it
had no effect on CYP2C8 and CYP2C9 activity at the highest
concentration tested (100 µM), weakly inhibited CYP1A2,
CYP2C19, and CYP2D6 activity (IC50 > 100 µM), and
moderately inhibited CYP2A6 and CYP3A4 activity (IC50
≈
30-40 µM). Compound 11q was rapidly metabolized in
monkey and rat, moderately metabolized in dog, and minimally
metabolized in mouse and human liver microsomes. It was
nonmutagenic in Ames and genotoxicity assays.
The rat pharmacokinetic profile of 11q (Table 4) was
characterized by high apparent volume of distribution (Vss) with
high systemic clearance (7.4 L h-1 kg-1) approximately twice

5538 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Letters
(2) Unsworth, C. D.; Molinoff, P. B. Characterization of a 5-hydroxy-
tryptamine receptor in mouse neuroblastoma N18TG2 cells. J.
Pharmacol. Exp. Ther. 1994, 269, 246-255.
(3) Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.;
Lachowicz, J. E.; Meltzer, H. Y.; Sibley, D. R.; Roth, B. L.; Hamblin,
M. W. Cloning, characterization, and chromosomal localization of a
human 5-HT6 serotonin receptor. J. Neurochem. 1996, 66, 47-56.
(4) Sebben, M.; Ansanay, H.; Bockaert, J.; Dumuis, A. 5-HT6 receptors
positively coupled to adenylyl cyclase in striatal neurones in culture.
NeuroReport 1994, 5, 2553-2557.
(5) Sleight, A. J.; Boess, F. G.; Bos, M.; Bourson, A. The putative 5-ht6
receptor: localization and function. Ann. N. Y. Acad. Sci. 1998, 861,
91-96.
(6) Woolley, M. L.; Marsden, C. A.; Fone, K. C. 5-ht6 receptors. Curr.
Drug Targets: CNS Neurol. Disord. 2004, 3, 59-79.
Figure 4. Scheduled-induced polydipsia in rats after oral dosing with
11q: (/) P < 0.05 compared to vehicle treatment.
(7) Sleight, A. J.; Boess, F. G.; Bos, M.; Levet-Trafit, B.; Riemer, C.;
Bourson, A. Characterization of Ro 04-6790 and Ro 63-0563: potent
and selective antagonists at human and rat 5-HT6 receptors. Br. J.
Pharmacol. 1998, 124, 556-562.
(8) Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson, K.; Gager,
T.; Grassam, H. L.; Jeffrey, P. M.; Joiner, G. F.; King, F. D.;
Middlemiss, D. N.; Moss, S. F.; Newman, H.; Riley, G.; Routledge,
C.; Wyman, P. 5-Chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-
methyl-2-benzothiophenesulfon-amide (SB-271046): a potent, selec-
tive, and orally bioavailable 5-HT6 receptor antagonist. J. Med. Chem.
1999, 42, 202-205.
(9) Meneses, A. Role of 5-HT6 receptors in memory formation. Drug
News Perspect. 2001, 14, 396-400.
(10) Woolley, M. L.; Bentley, J. C.; Sleight, A. J.; Marsden, C. A.; Fone,
K. C. A role for 5-ht6 receptors in retention of spatial learning in
the Morris water maze. Neuropharmacology 2001, 41, 210-219.
(11) Tsai, Y.; Dukat, M.; Slassi, A.; MacLean, N.; Demchyshyn, L.;
Savage, J. E.; Roth, B. L.; Hufesein, S.; Lee, M.; Glennon, R. A.
N1-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists. Bioorg.
Med. Chem. Lett. 2000, 10, 2295-2299.
Figure 5. Microdialysis studies demonstrate that acute 11q administra-
tion elevates GABA levels in the rat frontal cortex. First and second
arrows represent time of 5-HT6 antagonist and 11q administration,
respectively: (/) P < 0.05 compared to vehicle treatment; ([) vehicle;
(9) 11q (10 mg/kg sc); (0) 2 (10 mg/kg, sc) then 11q (10 mg/kg, sc).
(12) Mattsson, C.; Sonesson, C.; Sandahl, A.; Greiner, H. E.; Gassen,
M.; Plaschke, J.; Leibrock, J.; Bottcher, H. 2-Alkyl-3-(1,2,3,6-
tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists.
Bioorg. Med. Chem. Lett. 2005, 15, 4230-4234.
(13) Cole, D. C.; Ellingboe, J. W.; Lennox, W. J.; Mazandarani, H.; Smith,
D. L.; Stock, J. R.; Zhang, G.; Zhou, P.; Schechter, L. E. N1-
Arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives
are potent and selective 5-HT6 receptor antagonists. Bioorg. Med.
Chem. Lett. 2005, 15 (2), 379-383.
(14) Russell, M. G.; Baker, R. J.; Barden, L.; Beer, M. S.; Bristow, L.;
Broughton, H. B.; Knowles, M.; McAllister, G.; Patel, S.; Castro, J.
L. N-Arylsulfonylindole derivatives as serotonin 5-HT(6) receptor
ligands. J. Med. Chem. 2001, 44, 3881-3895.
(15) Bernotas, R.; Lenicek, S.; Antane, S.; Zhang, G. M.; Smith, D.;
Coupet, J.; Harrison, B.; Schechter, L. E. 1-(2-Aminoethyl)-3-
(arylsulfonyl)-1H-indoles as novel 5-HT(6) receptor ligands. Bioorg.
Med. Chem. Lett. 2004, 14, 5499-5502.
(16) Di, L.; Kerns, E. H. Application of pharmaceutical profiling assays
for optimization of drug-like properties. Curr. Opin. Drug. DiscoVery
DeV. 2005, 8, 495-504.
(17) Di, L.; Kerns, E. H.; Fan, K.; McConnell, O. J.; Carter, G. T. High
throughput artificial membrane permeability assay for blood-brain
barrier. Eur. J. Med. Chem. 2003, 38, 223-232.
(18) Kerns, E. H.; Di, L.; Petusky, S.; Farris, M.; Ley, R.; Jupp, P.
Combined application of parallel artificial membrane permeability
assay and Caco-2 permeability assays in drug discovery. J. Pharm.
Sci. 2004, 93, 1440-1453.
(19) Hogg, S.; Dalvi, A. Acceleration of onset of action in schedule-
induced polydipsia: combinations of SSRI and 5-HT1A and 5-HT1B
receptor antagonists. Pharmacol. Biochem. BehaV. 2004, 77, 69-75.
modify food or water intake when administered under non-SIP
conditions, suggesting that the effects are specific for compulsive
behaviors.
In vivo microdialysis experiments were used to explore the
neurochemical effects of acute treatment with 11q in the rodent
brain (Figures 4 and 5). In the frontal cortex, 11q (10 mg/kg,
sc) significantly increased extracellular GABA concentrations
without altering levels of glutamate or norepinephrine (data not
shown). Subsequent studies showed that the GABAergic effects
of 11q were blocked by pretreatment with the 5-HT6 antagonist
2 (10 mg/kg, sc), further implicating 5-HT6 receptor mechanisms
in mediating this response.
In conclusion, a novel 5-HT6 receptor agonist with >50-fold
selectivity against serotonergic and other receptors has been
identified. On the basis of its acceptable physiochemical
properties and pharmacokinetic profile, 11q has been studied
in vivo and initial findings suggest a role for 5-HT6 agonists in
treating OCD, considered a type of anxiety disorder.
Supporting Information Available: Experimental procedures
for the synthesis and characterization of 11q and analogues; binding,
functional, physiochemical, and PK results; and details of in vivo
experiments. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) Monsma, F. J., Jr.; Shen, Y.; Ward, R. P.; Hamblin, M. W.; Sibley,
D. R. Cloning and expression of a novel serotonin receptor with high
affinity for tricyclic psychotropic drugs. Mol. Pharmacol. 1993, 43,
320-327.
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