Novel 2-aminotetralin and 3-aminochroman derivatives as selective serotonin 5-HT7 receptor agonists and antagonists

Article abstract of DOI:10.1021/jm0498102

The understanding of the physiological role of the G-protein coupled serotonin 5-HT₇ receptor is largely rudimentary. Therefore, selective and potent pharmacological tools will add to the understanding of serotonergic effects mediated through t

Full text of DOI:10.1021/jm0498102

J . Med. Chem. 2004, 47, 3927-3930
3927
Novel 2-Am in otetr a lin a n d
3-Am in oCh r om a n Der iva tives a s
Selective Ser oton in 5-HT7 Recep tor
Agon ists a n d An ta gon ists
Pa¨r Holmberg,† Daniel Sohn,‡ Robert Leideborg,‡
Patrizia Caldirola,†,# Pavel Zlatoidsky,†,
Sverker Hanson,‡ Nina Mohell,‡,# Susanne Rosqvist,‡
Gunnar Nordvall,‡ Anette M. J ohansson,*,†,| and
Rolf J ohansson*,†,‡
Organic Pharmaceutical Chemistry,
Uppsala University, Uppsala Biomedical Centre, Box 574,
SE-751 23 Uppsala, Sweden, Local Discovery Research Area
CNS & Pain Control, AstraZeneca R&D So¨derta¨lje,
SE-15185 So¨derta¨lje, Sweden, Biovitrum AB,
F igu r e 1. 5-HT7 antagonists and agonists.
SE-112 76 Stockholm, Sweden, Preclinical R&D,
AstraZeneca R&D Lund, SE-22187 Lund, Sweden, and
Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, Indiana 46285
Sch em e 1a
Received March 7, 2004
Abstr a ct: The understanding of the physiological role of the
G-protein coupled serotonin 5-HT7 receptor is largely rudi-
mentary. Therefore, selective and potent pharmacological tools
will add to the understanding of serotonergic effects mediated
through this receptor. In this report, we describe two com-
pound classes, chromans and tetralins, encompassing com-
pounds with nanomolar affinity for the 5-HT7 receptor and
with good selectivity. Within theses classes, we have discovered
both agonists and antagonists that can be used for further
understanding of the pharmacology of the 5-HT7 receptor.
The functional significance of the serotonin 5-HT7
receptor is largely unknown. However, the distribution
pattern of the 5-HT7 receptor mRNA in both the central
nervous system and in the periphery has led to a
number of suggestions of the physiological role of this
G-protein coupled receptor. The presence of mRNA in
the thalamus and hypothalamus combined with the
high affinity of antipsychotic drugs for the 5-HT7
receptor have implicated the importance of this subtype
in psychiatric disorders.1 Expression of 5-HT7 receptors
has also been reported in limbic and cortical areas of
rodent brains where it is localized on glutamatergic
neurons,2a-c and therefore signaling of the receptor has
been linked to memory and learning processes. Fur-
thermore, the receptor has been associated with central
functions such as circadian time keeping,1 epilepsy,2b
pain perception,3 and migraine.4 A role for peripherally
located 5-HT7 receptors in gastrointestinal function5 has
been suggested.
a
Reagents: (a) EtCHO, NaBH3CN, MeOH; (b) BBr3, CH2Cl2;
(c) (CF3SO3)2O, Et3N, CH2Cl2; (d) ArB(OH)2, (PPh3)4Pd, Na2CO3,
PhMe, EtOH; (e) TFAA, Et3N, CH2Cl2; (f) AcOH, HCl, ∆; (g)
HCHO, NaBH3CN, MeOH.
selective 5-HT7 receptor agonists have emerged even
though some nonselective 5-HT7 agonists (5-6)10,11 are
reported. In this letter, we communicate the biochemical
features of a number of 8-substituted-3-aminochromans
(3,4-dihydro-2H-1-benzopyrans) and 5-substituted-2-
aminotetralins with high affinity and good selectivity
for the 5-HT7 receptor. These novel structures have effi-
cacies ranging from antagonists to full agonists, making
them useful tools for disclosing the intricacies of this
the most recently described serotonergic receptor.The
tetralin derivatives were obtained from commercially
available (S)-5-methoxy-2-aminotetralin (Scheme 1).
Reductive alkylation with propanal and NaBH3CN
The lack of further insight into the pharmacology of
the 5-HT7 receptor has been hampered by the absence
of chemical tools. In recent time, antagonists such as
1-46-9 with nanomolar affinity and selectivity toward
selected receptors have appeared. Still, no potent and
* Address correspondence to Rolf J ohansson, Tel.: +46 8 553 27532,
Fax.: +46 8 553 24220, E-mail: rolf.johansson@astrazeneca.com.
† Uppsala University.
‡ AstraZeneca R&D So¨derta¨lje.
#
Biovitrum AB.
AstraZeneca R&D Lund.
| Eli Lilly and Company.
10.1021/jm0498102 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/29/2004

3928 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16
Letters
Sch em e 2a
Sch em e 3a
a
Reagents: (a) CH2dCHCN, 1,4-diazabicyclo[2.2.2]-octane; (b)
NaOH (10% in H2O); (c) (PhO)2P(O)N3, Et3N, HCl; (d) BnNH2,
NaBH3CN, AcOH; (e) BnBr, KI, K2CO3; (f) L-dibenzoyltartaric acid,
H2O/1,2-dichloro-ethane (1:2); (g) HCOONH4, Pd(C); (h) EtCHO
or HCHO, NaBH3CN, Montmorillonite K-10; (i) Me2SBF3; (j)
(CF3SO2)2O, Et3N; (k) (PPh3)4Pd, (2,6-(MeO)2PhB(OH)2.
a
Reagents: (a) n-BuLi, TMEDA, THF, Bu3SnCl; (b) i. (dba)3Pd2,
Ph3As, CuI, ArI, DMF. ii. hν. iii. separation by chromatography.
afforded (S)-5-methoxy-2-(dipropylamino)tetralin (7),
which was demethylated by BBr3 in CH2Cl2 at low
temperature to give 8.
were obtained by Suzuki coupling of triflates 24a and
24b with (2,6-dimethoxyphenyl)boronic acid, respec-
tively.
Phenol 8 was converted to the triflate (trifluorometh-
anesulfonic acid) by reaction with triflic anhydride. The
triflate was subjected to Suzuki cross-coupling reactions
to afford the target (S)-5-aryl-2-(dipropylamino)tetra-
lins, 10a -d . To allow for the N-group(s) to be varied at
a later stage, a slightly different route was also devel-
oped. (S)-5-Methoxy-2-aminotetralin was converted into
the trifluoroacetamide 11, followed by demethylation to
phenol 12 and a subsequent triflation afforded 13. The
5-aryl substituent was introduced, as above, using the
Suzuki coupling reaction. Acidic hydrolysis of the N-
trifluoroacetmide gave primary amine 10e, which was
reductively alkylated to afford the desired (S)-5-aryl-2-
(dimethylamino)tetralin.
The novel compounds were evaluated for their affinity
to the 5-HT7, 5-HT1A, and D2A receptors, respectively,
according to methods previously described,9,13,15-19 and
the results are summarized in Table 1. Selected com-
pounds were also tested for affinities to a larger number
of receptors and ion channels (Table 2).14 In brief, the
compounds were tested for their ability to displace [3H]-
raclopride from mouse fibroblast (Ltk-) cells expressing
the human D2A receptor. Affinity for the 5-HT1A receptor
was determined in CHO cells expressing the human re-
ceptor or in rat hippocampal cells, using [3H]-8-OH-DP-
AT as the ligand. The affinity of the compounds for the
rat 5-HT7 receptor was measured in CHO- or Sf9-cells
using [3H]-5-HT as the ligand. Efficacy at the rat 5-HT7
receptor was obtained by measuring the effect of cAMP
production in CHO cells in relation to the effect elicited
by 5-HT.9 Compounds 1-4 and the corresponding
literature data are included for comparison (Table 1).
The biological results of the present series of com-
pounds show that the dimethylaminotetralins and the
dipropylaminotetralins as well as the corresponding
chromans, gave ligands with high affinity for the 5-HT7
receptor, whereas the primary amines are of lower
potency.
The interaction of the novel ligands with the 5-HT7
receptor is stereospecific favoring the (R)-chromans ((S)-
tetralins), giving eudismic ratios of approximately 130
((S)-17b vs. (R)-17b). Selectivity toward the 5-HT1A
receptor was accomplished by subtle changes of the
5-aryl substituent (8-aryl in the chromans). The intro-
duction of a single ortho methoxy substituent reduces
the affinity for the 5-HT1A receptor 8-13 times, while
the affinity for the 5-HT7 receptors is unchanged
(compare tetralins 10a and 10b and chromans 17a and
17b). Further introduction of a second ortho methoxy
substituent (10d and 17d ) substantially reduces the
affinity for the 5-HT1A receptor while only marginally
affecting the binding to the 5-HT7 receptor. It thus
seems as the ortho substituents by forcing the 5- (or 8-)-
The C8-substituted (R)- or (S)-3-(dipropylamino)-
chromans were prepared by two different routes. In the
first route, the (R)- or (S)-enantiomer of a mixture of
endo and exo-[η6-3-(dipropylamino)chroman]-Cr(CrO)3
(15) was reacted with n-butyllithium and tributyltin
chloride to give the corresponding 8-tributylstannane
16 (Scheme 2). The 8-aryl substituent was then intro-
duced by Stille coupling reactions with the appropriate
iodoarene followed by photolytic cleavage of the chro-
mium complex to give a mixture of the 8-aryl (17a -c)
and the 8-aroyl (18a -c) derivatives. The target 8-aryl
compounds were obtained by flash chromatography.
12
The second route starts with a base-catalyzed Michael
addition of 2-hydroxy-3-methoxybenzaldehyde to acryl-
onitrile, followed by a ring-closing condensation to afford
the unsaturated nitrile 19. The nitrile was hydrolyzed
to the carboxylic acid followed by a Curtius rearrange-
ment to give ketone 20. Reductive amination and
N-alkylation gave the N,N-dibenzyl derivative 21, which
after fractional crystallization as the L-dibenzoyltartrate
gave the (R)-enantiomer 22 in an enantiomeric purity
of 99% ee. Pd-catalyzed N,N-debenzylation followed by
reductive alkylation and demethylation gave phenols
23a -b, which were treated with triflic anhydride to give
triflates 24a -b . The target compounds 17d and 17e

Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16 3929
Ta ble 1. In Vitro Binding Affinities of the Novel Derivatives to 5-HT7, 5-HT1A, and D2A Receptors Labeled by [3H]5-HT,
[3H]8-OH-DPAT, and [3H]Raclopride and Effects on 5-HT7-Mediated Stimulation of cAMP Production in CHO Cells Expressing Rat
5-HT7 Receptors
Ki (nM)a
compd
Ar
R′
struct
5-HT7
5-HT1A
D2A
Ki ratio 5-HT1A/5-HT7
efficacyb(%)
10a
10b
10c
10d
10e
10f
Ph
2-MeOPh
4-MeOPh
2,6-(MeO)2Ph
2,6-(MeO)2Ph
2,6-(MeO)2Ph
Ph
2-MeOPh
2-MeOPh
Pr
Pr
Pr
Pr
H
Me
Pr
Pr
Pr
Pr
Pr
Me
A
A
A
A
A
A
B
B
C
B
B
B
3.38 ( 0.53
1.73 ( 0.28
12.4 ( 0.6
7.9 ( 0.42
78.7 ( 5.1
2.55 ( 0.45
2.92 ( 1.11
2.7 ( 0.35
364 ( 37
12.6 ( 2.3
6.44 ( 1.39
5.29 ( 0.09
6.46
0.87 ( 0.28
11.7 ( 1.7
1.49 ( 0.36
347 ( 198
>1000
1420 ( 210
1.23 ( 0.05
10.3 ( 1.6
680 ( 110
1.31 ( 0.15
174 ( 15
>1000
NTc
NT
NT
1210 ( 10
NT
241 ( 46
106 ( 11
512 ( 110
2110 ( 440
741 ( 200
NT
0.26
6.8
0.12
44
>12.7
257
0.42
3.8
1.9
0.10
27
>189
79
100
100
100
<10
100
100
17a
(R)-17b
(S)-17b
17c
17d
17e
1d
4-MeOPh
2,6-(MeO)2Ph
2,6-(MeO)2Ph
91
154 ( 11
28 ( 3
antag
antag
antag
antag
NT
513
562
479
142
2e
1.99
2.24
3.79
282
214
37
3f
234
498
4g
a
The Ki-values are means ( standard errors of 2-3 experiments. The binding studies were performed essentially as described in
J ohansson et al.19 cAMP production in CHO-cells in % of 5-HT stimulated production. Antag ) antagonist. c NT ) not tested. See ref
b
d
6. e See ref 7. f See ref 8. See ref 9.
g
Ta ble 2. Receptor Binding Profile of 10d and 10f
amino)-tetralin (10d ) and 3-(dipropylamino)chroman
(17d ) are full agonists (100 and 154% of the effect of
5-HT, respectively) at the 5-HT7 receptor, the corre-
sponding dimethylamino substituted derivatives 10f
and 17e are antagonist or weak partial agonist, respec-
tively. The chroman derivatives appear to have a higher
efficacy than the corresponding tetralins. The dipropyl-
amino derivatives are all full agonists, whereas com-
pounds with a dimethylamino group show significantly
lower efficacy. The increase in volume and lipophilicity
of the N-substituents induces a dramatic change in
intrinsic activity without affecting affinity, indicating
that occupation of a propyl pocket is needed for G-
protein activation of the 5-HT7 receptor.
Two compounds, the agonist 10d and antagonist 10f,
showing high selectivity for the 5-HT7 receptor over
5-HT1A and D2 receptors, were profiled against 32 other
receptors and nine ion channels. The results show that
this structural class seems to be highly selective toward
other receptors and ion channels (Ki or IC50 > 1000 nM)
except for a few targets shown in Table 2. It is
noteworthy that the selectivity of 10d and 10f toward
the other 5-HT receptors tested is high with the excep-
tion of a moderate selectivity for 10f over the 5-HT5
receptor (24-fold).
Ki (nM)
10f
receptor
5HT7
5HT1A
5HT2A
5HT3
ligand
[3H]5-HT
tissue or cell
CHOr5HT7
10d
7.9
2.55
[3H]8-OH-DPAT CHOh5HT1A 347
1420
1340
>1000a
[3H]Ketanserin
[3H]GR-65630
rat cortex
rabbit ileum
muscularis
guinea pig
striatum
CHO cells
CHOr5HT6
rat striatum
LtkhD2A
rat cortex
rat cortex
rat cortex
rat cortex
1450
5HT4
[3H]GR-113808
>1000a,b
5HT5
5HT6
D1
[3H]LSD
65b
[3H]5-HT
>900
>1000a,b
[3H]SCH23390
[3H]Raclopride
[3H]Prazosin
[3H]RX821002
[3H]DHA
>1000 >1000
D2A
R1
R2
â
1210
>1000 3670
2090 188
241
>1000 >1000
>1000 >1000
muscarinic [3H]QNB
a
b
IC50 nM. The binding studies were performed by MDS
Pharma according to their standard protocols.
aryl group out of the plane of the tetralin (or chroman)
reduces favorable interactions with the 5-HT1A receptor.
The 4-methoxyphenyl (10c and 17c) and phenyl (10a
and 17a ) derivatives are equipotent at the 5-HT1A
receptors, while their affinity for 5-HT7 receptors is
reduced 4 times. Thus, the ligand binding site of the
5-HT7 receptor appears to be more restricted for sub-
stituents in the para position of the 5- (or 8-)-aryl group
than the corresponding site in the 5-HT1A receptor.
Interestingly, decreasing the size of the N-alkyl-
substituents from propyl to methyl increases the selec-
tivity for the 5-HT7 receptor 6-7-fold. This increase is
at least for the chromans and to some extent also for
the tetralins, due to the drop in affinity for the 5-HT1A
receptor supporting earlier studies suggesting the exist-
ence of a propyl pocket at this receptor.15 Not only is
the selectivity affected by varying the alkyl substitution
of the nitrogen group, but also the signal transduction
seems to be influenced by the choice of N-alkyl groups.
While the 2,6-dimethoxyphenyl substituted 2-(dipropyl-
The results presented herein show that structural
modifications of (S)-2-aminotetralin and (R)-3-ami-
nochroman give 5-HT7 ligands ranging from full ago-
nists to antagonists. Further, 10d has been identified
as a selective 5-HT7 receptor agonist and as such may
be used in future studies of the pharmacology/physiology
of this subtype of the serotonin family of receptors. A
full account of the SAR within these series will be
published in due course.
Ack n ow led gm en t. We thank Personal Chemistry
AB for providing the Smith microwave synthesizer.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the binding and functional assays and the synthetic

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