2-aryl tryptamines: Selective high-affinity antagonists for the h5-HT(2A) receptor

Article abstract of DOI:10.1016/S0960-894X(00)00557-6

A series of 2-aryl tryptamines have been identified as high-affinity h5-HT(2A) antagonists. Structure-activity relationship studies have shown that h5-HT(2A) affinity can be attained via modifications to the tryptamine side chain and that selectivity over h5-HT(2C) and hD₂ receptors can be controlled by suitable C-2 aryl groups. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00557-6

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2697±2699
2-Aryl Tryptamines: Selective High-Anity Antagonists
for the h5-HT2A Receptor
Graeme I. Stevenson,* Adrian L. Smith, Stephen Lewis, Stephen G. Michie,
Joseph G. Neduvelil, Smita Patel, Rosemarie Marwood, Shil Patel and Jose L. Castro
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow,
Essex CM20 2QR, UK
Received 26 June 2000; revised 18 August 2000; accepted 15 September 2000
AbstractÐA series of 2-aryl tryptamines have been identi®ed as high-anity h5-HT2A antagonists. Structure±activity relationship
studies have shown that h5-HT2A anity can be attained via modi®cations to the tryptamine side chain and that selectivity over h5-
HT2C and hD2 receptors can be controlled by suitable C-2 aryl groups. # 2000 Elsevier Science Ltd. All rights reserved.
Historically, the pathophysiology of schizophrenia has
involved the `serotonin hypothesis',1 based on the
observation that LSD induces schizophrenia-like e€ects
in man, and the `dopamine hypothesis',1 arising from
the apparent e€ectiveness of typical antipsychotics in
treating the core symptoms of the disease. Typical anti-
psychotic drugs are thought to act mainly by hD2
receptor blockade which is believed to be associated
with extrapyramidal side e€ects (EPS), such as tardive
dyskinesia. With the introduction of atypical anti-
psychotics such as clozapine, which has greater anity
for h5-HT2A, h5-HT2C, h5-HT6 and h5-HT7 receptors
than for hD2 and shows a much lower incidence of EPS,
the `serotonin hypothesis' has gained ground in the
understanding and treatment of schizophrenia. Since
the development of more selective h5-HT2A antagonists
such as mianserin2 1 and the highly h5-HT2A selective
MDL 1009073 2, currently in phase III clinical trials for
chronic schizophrenia, attention has focused on the
h5-HT2A receptor as a therapeutic target.
We recently reported the development of a novel solid-
phase synthesis which led to the identi®cation of the
2-phenyltryptamine derivative 3 as a high-anity h5-
HT2A antagonist showing good selectivity over h5-HT2C
and hD2 receptors.4 Recent developments in the sero-
tonin area have indicated that C-2 substituted trypta-
mines are tolerated at 5-HT receptors5 and realising the
potential of 3 we embarked on a program to rapidly
explore the SAR of 2-phenyl tryptamines.
In order to facilitate the rapid development of SAR
around 3, we initially exploited the established solid-
phase methodology. This approach is shown in Scheme 1.
The resin bound intermediate 4 can be prepared easily
from tryptophol in ®ve steps at around 0.6±0.8 mmol/g.4
Initial attempts to introduce the C-2 aryl function by
coupling with a boronic acid derivative often resulted in
incomplete conversion to the desired product and sig-
ni®cant decreases in resin loading, the latter being
attributed to the basic conditions required for this type
of reaction. If, however, the coupling was based upon
the reaction of an aryl stannane with 4, the reaction was
neutral and no decrease in loading was observed. Good
conversion rates could be achieved with one or two
couplings. Removal of the THP group from 5 a€orded
the resin bound alcohol; activation as the tri¯ate and
*Corresponding author. Fax: +44-1279-440187; e-mail: graeme_
stevenson@merck.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00557-6

2698
G. I. Stevenson et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2697±2699
displacement with a nucleophilic amine then gave 6.
Finally, the products 7 were cleaved from the resin
using hot acetic acid, and puri®ed by ion exchange
chromatography.6
tryptophol (0.042 mmol) and Et3N (0.17 mmol) in 1,2-
dichloroethane (1.0 mL) was dispensed into a 8 mL tube
containing a ¯ea stirrer. The tube was sealed under
nitrogen with a septum top and cooled by placing in a
suitable rack in a cold bath. Tri¯uoromethanesulfonic
anhydride (0.06 mmol) was then dispensed to each tube
using a repeating syringe.
After 30 min, the appropriate amine HNR2 (100 mL of a
1.0 mmol solution in DCE) was added and the reaction
allowed to warm to room temperature over 3 h. The
crude products 12 were isolated following treatment
with methylisothiocyanate polystyrene resin10 to remove
excess amine, ®ltration and solvent removal. Deprotec-
tion under acidic conditions followed by ion exchange
chromatogaphy6 gave the ®nal products 13.
Table 1 shows the initial SAR development in the
tryptamine side chain. Ring contraction to either the
pyrrolidine 14 or cyclobutane 15 analogues resulted in a
Scheme 1. Reagents: (i) Pd(PPh3)4, ArSnR3, THF, 70 ꢀC; (ii) PPTS,
10% EtOH/DCE; (iii) Tf2O, 2,6-DitButyl-4-methylpyridine; (iv)
HNR2 DCE; (v) AcOH, 110 ꢀC.
Table 1. E€ect of amine variations on h5-HT2A anity and selectivity
In the cases where the introduction of the C-2 aryl
group failed using the solid-phase route (Table 2, entries
29±32), a second, solution-phase route was developed as
shown in Scheme 2.
Ki (nM)
a,b,c
d
e
Example
NR2
h5-HT2A
2.60
h5-HT2C
hD2
3
268
896
14
15
9
260
>1 mM
>1 mM
44
>1 mM
16
17
0.18
4.0
36
21
230
290
18
19
0.26
29
92
>3 mM
>3 mM
>3 mM
Scheme 2. Reagents: (i) Pd(PPh3)4, ArB(OH)2, DMF, 2 N Na2CO3;
(ii) PPTS, 10% EtOH/DCE; (iii) Tf2O, 2,6-DitButyl-4-methylpyridine,
DCE 78 ꢀC; (iv) HNR2, DCE; (v) PS-NCS, DCE; (vi) HCl, MeOH.
20
21
22
4.4
180
160
11
>1 mM
>1 mM
85
In contrast to the route shown in Scheme 1, introduc-
tion of the C-2 aryl group by coupling with a boronic
acid was found to be satisfactory both in terms of yield
and purity. Conversion of 8 to 9 was achieved via cou-
pling with the appropriate boronic acid followed by
deprotection to give the alcohol 10. Activation of 10
was achieved by conversion to the tri¯ate 11 at 78 ꢀC
followed by displacement with nucleophilic amines.
Initial attempts to preform 11 in bulk and dispense in a
parallel synthesis fashion failed. To overcome this, the
tri¯ation itself was carried out in a parallel fashion
using 8 mL septum capped tubes as the reaction vessels.
In a typical procedure, a solution of the appropriate
2.8
0.14
aAll compounds antagonised PI accumulation stimulated by 1 mM
5HT in CHO cells expressing h5-HT2A receptors.
bBinding anities are quoted as Ki values and are the geometric mean
of at least two experiments.
cDisplacement of [3H]-ketanserin from CHO cells expressing h5-HT2A
receptors.7
dDisplacement of [3H]-mesulergine from CHO cells expressing h5-
HT2C receptors.8
eDisplacement of [3H]-spiperone from CHO cells expressing hD2
receptors.9

G. I. Stevenson et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2697±2699
2699
loss of h5-HT2A anity and overall selectivity. Replace-
ment of the piperidine of 3 with both enantiomers of a-
methyl piperidine (16, 17) demonstrated that it was
possible to achieve high h5-HT2A anity, albeit with
somewhat reduced selectivity over hD2, and that there
was some of enantiodi€erentiation in binding. High h5-
HT2A anity and selectivity could be achieved with the
side chain derived from (S)-2-(methoxymethyl)pyrrolidine
18, the enantiomer of which, 19, was completely inactive
(cf. 17). Surprisingly, it was the simple dialkylamines 20,
21 and 22, which had the best pro®les, with 22 having 75
fold selectivity over h5-HT2C and 600-fold selectivity
over hD2, whilst showing a 20-fold improvement in a-
nity over 3 at h5-HT2A. Having optimized the tryptamine
side chain, we turned our attention to the C-2 aryl group.
Using 22 as a baseline, it can be seen from the results in
Table 2 that whilst replacement of the C-2 phenyl group
of 22 with furan (23) is not tolerated, other changes in
the nature of the C-2 aryl group had varying e€ects on
h5-HT2A anity. Replacement of the C-2 phenyl group
of 22 with thiophene 24 caused a decrease in h5-HT2A
anity resulting in decreased selectivity over hD2.
Introduction of a 4-chloro substituent (25) resulted in a
loss in h5-HT2A anity and decreased selectivity,
whereas the 4-cyano analogue 26 shows signi®cantly
increased hD2 anity resulting in reversed selectivity.
This indicates that the substitution pattern of the C-2
aryl function has a profound e€ect upon selectivity. As
the ¯uoro isomers 27, 28 and 29 possess subnanomolar
h5-HT2A anity and generally excellent selectivity over
h5-HT2C and hD2, the e€ect seen in 26 is not simply
that of an electron de®cient ring. It would also appear
that substitution at the C-3 position of the aryl ring
o€ers the best h5-HT2A anity/selectivity pro®le.
Alternative electron withdrawing groups at this posi-
tion, such as nitrophenyl (30) or tri¯uoromethyl (31)
maintain h5-HT2A anity but have reduced selectivity
over hD2. However, excellent selectivity over hD2 can
be achieved by the introduction of a 3,5 bis(tri-
¯uoromethyl)phenyl group at C-2 (32).
Table 2. E€ect of aryl variations on h5-HT2A anity and selectivity
Ki (nM)
a,b,c
d
e
Example
Ar
h5-HT2A
0.14
h5-HT2C
hD2
In conclusion we have shown that 2-phenyl tryptamine
can be used as a template for the design of high-anity
h5-HT2A antagonists. Subnanomolar h5-HT2A anity
and selectivity over h5-HT2C and hD2 can be achieved
via the tryptamine side chain and modi®cation of the
C-2 aryl group.
22
11
85
23
24
>1 mM
>1 mM
>1 mM
1.7
120
78
25
26
27
3.5
36
250
0.42
17
2.6
160
31
References and Notes
0.43
1. Kane, J. M. In Schizophrenia From Mind to Molecule;
Andreasen, N. C., Ed.; American Psychiatric, 1994, pp 173±
187.
2. Alexander, B. S.; Wood, M. D. J. Pharm. Pharmacol. 1987,
39, 664.
28
29
30
31
0.30
0.08
0.14
0.13
30
8.4
36
12
150
68
3. Sorbera, L. A.; Silvestre, J.; Castaner, J. Drugs Future 1998,
23, 955.
4. Smith, A. L.; Stevenson, G. I.; Lewis, S.; Patel, S.; Castro,
J. L. Bioorg. Med. Chem. Lett. 2000, 10, 2693.
5. Glennon, R. A.; Lee, M.; Rangsetty, J. B.; Dukat, M.;
Roth, B. L.; Savage, J. E.; McBride, A.; Rauser, L.; Hufeisen,
S.; Lee, D. K. H. J. Med. Chem. 2000, 43, 1011.
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Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357.
7. Berg, K. A.; Clarke, W. P.; Salistad, C.; Saltzman, A.;
Maayani, S. Mol. Pharmacol. 1994, 46, 477.
39
17
32
0.19
15
187
8. Freedman, S.; Harley, E. A.; Iversen, L. L. Br. J. Pharma-
col. 1988, 93, 437.
aAll compounds antagonised PI accumulation stimulated by 1 mM
5HT in CHO cells expressing h5-HT2A receptors.
bBinding anities are quoted as Ki values and are the geometric mean
of at least two experiments.
9. Patel, S.; Freedman, S.; Chapman, K. L.; Emms, F.;
Fletcher, A. E.; Knowles, M.; Marwood, R.; McAllister, G.;
Myers, J.; Patel, S.; Curtis, N.; Kulagowski, J. J.; Leeson, P.
D.; Ridgill, M.; Graham, M.; Matheson, S.; Rathbone, D.;
Watt, A. P.; Bristow, L. J.; Rupniak, N. M. J.; Baskin, E.;
Lynch, J. J.; Ragan, C. I. J. Pharm. Exp. Ther. 1997, 283, 634.
10. Novobiochem; methylisocyanate polystyrene HL (200±
400 mesh) >1.0 mmol/g.
cDisplacement of [3H]-ketanserin from CHO cells expressing h5-HT2A
receptors.7
dDisplacement of [3H]-mesulergine from CHO cells expressing h5-
HT2C receptors.8
eDisplacement of [3H]-spiperone from CHO cells expressing hD2
receptors.9