Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence for a second binding mode at 5-HT6 for antagonism

Article abstract of DOI:10.1016/j.bmcl.2010.03.110

A series of 5-HT₆ ligands derived from (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin was prepared that yielded several non-basic analogs having sub-nanomolar affinity. Ligand structure-activity relationships, receptor point mutation studies, and molecular modeling of these novel ligands all combined to reveal a new alternative binding mode to 5-HT₆ for antagonism.

Full text of DOI:10.1016/j.bmcl.2010.03.110

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3436–3440
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence
for a second binding mode at 5-HT6 for antagonism
*
Ralph N. Harris III , Russel S. Stabler, David B. Repke, James M. Kress, Keith A. Walker, Renee S. Martin,
Julie M. Brothers, Mariola Ilnicka, Simon W. Lee, Tara Mirzadegan
Roche Palo Alto LLC, 3431 Hillview Ave., Palo Alto, CA 94304, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 5-HT6 ligands derived from (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin was prepared that
yielded several non-basic analogs having sub-nanomolar affinity. Ligand structure–activity relationships,
receptor point mutation studies, and molecular modeling of these novel ligands all combined to reveal a
new alternative binding mode to 5-HT6 for antagonism.
Received 17 February 2010
Revised 26 March 2010
Accepted 26 March 2010
Available online 1 April 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
5-HT6 neutal antagonist
Non-basic ligands
Binding model
1,6-Disubstituted-tetralins
Receptor point mutation
The 5-HT6 receptor is a member of the super family of seven
trans-membrane G-protein-coupled receptors and the small group
of 5-HT receptors that are positively linked to adenylyl cyclase.1 It
occurs almost exclusively in the brain and is most densely local-
ized in those areas of the limbic and cortical regions that are asso-
ciated with cognition. Although the functional role of 5-HT6 is
somewhat controversial, its physiological distribution and binding
characteristics to several important tricyclic antidepressants and
atypical antipsychotics implicate it in diverse CNS disorders
including psychosis,1 affective disorders,1b,2 anxiety,3 epilepsy,4
obesity,5 and most compellingly, cognition and memory disor-
ders.5a,c,6 Animal behavioral and micro-dialysis studies support a
regulatory role for 5-HT6 in cholinergic and glutamatergic path-
ways suggesting 5-HT6 antagonists may have therapeutic utility
for the treatment of cognitive deficits in Alzheimer’s disease and
schizophrenia.6a,7
brane helix 3 aspartic acid 106 (TM3 Asp106) and that is attached
by no more than 5-atom distance to (ii) a flat aromatic core ring
system. To the core ring system, (iii) a second distal pendant aro-
matic ring is attached by a linker that must be tetrahedral in geom-
etry and is most effectively accommodated by sulfonyl. As these
features are quite simplistic, it is not surprising that so many dif-
ferent active molecular scaffolds have been identified, and yet a
model for binding remains nebulous. The first attempt at a binding
model was proposed by Bromidge9 and included an ionic interac-
tion between ligand amine and TM3 Asp106 with additional aro-
matic
p-stacking interactions involving Phe277 and Trp281.
Subsequently, Glennon and co-workers10 proposed two separate
binding orientations for agonists and antagonists with both orien-
tations sharing the TM3 Asp106 site for positive ionizable interac-
tions. The other major interactions for antagonism in this model
were implied to occur between the pendant arylsulfonyl ring and
While there has been extensive effort with considerable pro-
gress in identifying functional ligands for 5-HT6 since its discov-
ery,1a there remains some controversy over the mode by which
ligands bind at the receptor site. Indeed, the molecular diversity
of active templates8 for 5-HT6 has caused more conundrum than
clarification. To date, the structural features that are most com-
monly recognized for antagonist binding to 5-HT6 are three main
elements: (i) a positive ionizable anchoring group, usually in the
form of an amine, that interacts with the receptor at trans-mem-
TM6 Gln291 (H-bond) and TM7 Phe302 (
and co-workers11 have proposed a similar model to Glennon’s with
the addition of hydrophobic -stacking elements between the li-
gand core ring and TM6 Phe284, and the ligand pendant ring with
TM5 Phe188. Until now, all of these models have been well consis-
tent with ligand structure–activity relationships (SAR) and the
structural characteristics that are recognized for binding.
A radioligand binding screen of our in house compound libraries
turned up the di-substituted tetralin 1 (Fig. 1) as a very potent and
selective 5-HT6 antagonist, but with pharmacokinetic (PK) proper-
ties that included very poor brain penetration and a CYP2D6 IC50 of
less than 50 nM, both of which were attributed to the highly polar
p-stacking). Campillo
p
* Corresponding author. Tel.: +1 650 257 7098.
E-mail address: ralphharris@comcast.net (R.N. Harris).
0960-894X/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2010.03.110

R. N. Harris III et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3436–3440
3437
Table 1
polar head group
NH
NH
Binding to h5-HT6 by selected polar head group analogs of lead tetralin 1
H2N
X
pendant
ring
S
O
O
S
O
O
a
Compound
X
h5-HT6 (pKi)
1
NH
NH2
NH
CH3
1
9.8
Figure 1. Breakdown of regions of 1 for analog development.
HN
HN
2
3
9.2
9.5
guanidine. With the hope of finding a more PK compatible head
group for this template, we prepared a small selected group of ana-
logs (2–6, Table 1) designed to dissect the importance of the gua-
nidine for binding, and were highly encouraged to find that not
only was the guanidine non-essential, but that a simple non-basic
urea (6) provided comparable activity. Compound 6 was subse-
quently confirmed to completely inhibit 5-HT evoked response at
a recombinately expressed human 5-HT6 receptor. Herein, we re-
port our efforts to further optimize compound 1 with respect to
receptor binding and PK properties, all of which led to the discov-
ery of several non-basic functional ligands having sub-nanomolar
affinity. In addition, we offer clear evidence that they bind in a
manner separate from the traditional positive ionizable TM3
Asp106 site.
As shown in Figure 1, the lead template was divided into two
structural regions for analog development, the pendant ring and
the polar head group. A chiral synthesis (Scheme 1) was devised
that provided key intermediates as well as a means of determining
the absolute configuration of the active enantiomer, which ulti-
mately proved to be R. Thus, starting from the commercially avail-
able tetralone 7 (Scheme 1), iodide 9 was obtained in excellent
yield and was then converted to the chiral alcohol 10 by way of
asymmetric borane reduction using the conditions of Burkhardt
CH3
N
N
H
CH3
4
10.2
CH3
N
5
6
7.6
9.2
HN
HN
N
O
NH2
Affinities (pKi in Àlog M) were determined by radioligand binding with [3H] LSD
a
in membranes prepared from cells engineered to recombinantly express human 5-
HT6 receptors.
and Salunkhe.12 Key to the sequence was Mitsunobu reaction of
10 with inversion of configuration at the asymmetric center to give
tricarboxylate 11 which was hydrolyzed to the chiral acid 12, all
accomplished using the procedure of Hillier et al.13 Carboxylic acid
12 was then subjected to Curtius rearrangement followed by isocy-
anate hydrolysis to give amine salt 14 which after recrystallization
O
O
O
OH
a
b
f,g,h
n
c
d
O
N
H2N
I
I
H
10
NH2 .HCl
9
7
8
C(CO2Et)3
NHBoc
COOH
NH2
NCO
e
i
j
I
I
I
I
I
11
12
14
13
X
k,l,m
Ar
Ar
S
S
15
17
16
O
O
O
O
X
NH2 . HCl
n,l
F
F
O
F
O
F
o
c,d,e,f,g,h,i
Ar
Ar
Ar
S
F
S
S
21
O
O
19
18
20
Scheme 1. Reagents and conditions: (a) 20% H2SO4, 90 °C, 100%; (b) NaNO2, KI, 94%; (c) (S)-2-Me-CBS-oxazaborolidine, PhNEt2ÁBH3, PhMe, 25 °C, 95%, 98% ee; (d) HC(CO2Et)3,
PMe3, DIAD, PhMe, À50 °C, 88%; (e) NaOH, MeOH–H2O, then HOAc, reflux, 84%; (f) oxalyl chloride, cat. DMF; (g) NaN3, acetone–H2O; (h) PhMe, 90 °C; (i) concd HCl, 90 °C, then
recrystallization from MeOH–EtOAc, 67%, 99.5% ee; (j) Boc2O, TEA, MeOH, 90%; (k) ArSH, Pd2(dba)3, xantphos, i-Pr2NEt, THF, 70–90%; (l) m-CPBA, CH2Cl2, 90–100%; (m) TFA,
100%; (n) electrophile, 70–90%; (o) ArSH, K2CO3, DMF, 55 °C, 70–80%.

3438
R. N. Harris III et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3436–3440
was upgraded to 99.5% ee. Protection of amine 14 as the tert-butyl
carbamate served to provide divergent intermediate 15 which was
coupled with various aryl thiols under the conditions of Itoh and
Mase.14 Oxidation and deprotection gave pendant ring analogs 16
that were then reacted with various electrophiles to give polar
head group analogs 17. Finally, starting from commercially avail-
able di-fluorotetralone 18, 8-fluoro analogs 21 were prepared
using a similar route but with variation in the order of sequence.
Table 2 lists the binding results to human 5-HT6 for analogs 16,
17, and 21. Remarkably, out of a total of 54 compounds, only six
have pKi less than 8 or affinity concentration greater than 10 nM.
Compounds 16g and h were the only two analogs that were essen-
tially inactive, and both compounds substitute pendant alkylsulfo-
nyl for arylsulfonyl. All previously proposed 5-HT6 binding models
analog 16d and the efficient p-stacking 3-indolyl analog 16n have
the highest affinities of all. The results for substituted amines 17b–
k indicate that the TM3 Asp106 site is capable of accommodating
basic amine substituents with varying size and polarity ranging
from a simple methyl ether (17f) to a highly polar built in salt
bridge (17g). These results all support a binding site that is both
versatile and accommodating with respect to ligand structure.
The most interesting results in Table 2 are represented by the
group of compounds 17l–ad. This subseries consists of amines that
have been acylated or sulfonylated to give non-basic polar head
groups. Even though this group of analogs is incapable of ionic
interactions under physiological conditions, they maintain for the
most part very high binding affinity. These results were surprising
and provided the first hint of a change in the ligand–receptor bind-
ing interactions. A striking SAR trend that provided a clue into the
nature of the non-ionic interactions is noted in the compound par-
ings 17l/17o, 17q/17r, and 17z/17aa. In each of these pairs, methyl
is substituted for hydrogen at the same nitrogen of the polar head
group, and in each case a corresponding reduction of at least one
log unit in affinity occurs. These results are in direct contrast to
those for the fully methylated amine 4 (Table 1) which actually
have implied the importance of hydrophobic
p-stacking interac-
tions,9–11 particularly with respect to the ligand pendant ring.
Here, the observation that cyclohexyl sulfone 16h is inactive while
the benzyl sulfone 16g retains only slight activity confirms that
aromatic
tion for binding, and that simple hydrophobic interactions without
-stacking is insufficient. Notably, the hydrophobic 3-fluorophenyl
p-stacking by the pendant ring is in fact a critical interac-
p
Table 2
Binding to h5-HT6 for analogs 16, 17, and 21
X
X
F
Ar
Ar
S
S
O
O
O
O
21
16, 17
Compd
X
Ar
Ph
pKia
Compd
X
Ar
pKia
16a
16b
16c
16d
16e
16f
16g
16h
16i
NH2
NH2
NH2
NH2
NH2
NH
NH2
NH2
NH2
9.8
9.6
9.4
10.1
8.4
9.3
6.8
<6
17u
17v
17w
17x
17y
17z
17aa
17ab
17ac
NHCOC(CH3)3
NHCOC(CH3)2OH
NHSO2CH3
N(CH3)SO2CH3
NHSO2CF3
3-F-Ph
3-F-Ph
3-F-Ph
3-F-Ph
3-F-Ph
3-F-Ph
3-F-Ph
3-F-Ph
3-F-Ph
8.4
8.7
9.7
9.4
7.5
9.9
8.4
9.0
8.7
3-HO-Ph
3-MeO-Ph
3-F-Ph
3-MeSO2-Ph
3-CN-Ph
PhCH2
NHSO2NH2
N(CH3)SO2NH2
NHSO2NHCH3
NHSO2N(CH3)2
c-C6H11
3-Pyrrolyl
9.5
16j
16k
16l
NHCH3
NH2
NH2
3-Pyrrolyl
1-Me-3-pyrrolyl
4-Pyrazolyl
9.8
8.1
8.7
O
O
17ad
3-F-Ph
7.5
S
N
16m
16n
17a
NH2
NH2
NH2
5-Thiazolyl
3-Indolyl
6-F-4-benzimidazolyl
9.1
10.3
8.3
H
N
17ae
3-F-Ph
10.0
HN
O
N
17b
17c
17d
NHCH2CONH2
N(CH3)CH2CONH2
NHCH2CONHCH3
3-F-Ph
3-F-Ph
3-F-Ph
10.0
8.9
9.0
O
H
N
17af
17ag
3-F-Ph
3-F-Ph
8.3
7.8
HN
HN
17e
17f
17g
NHCH2CH2OH
NHCH2CH2OCH3
NHCH2CH2CH2SO2OH
3-F-Ph
3-F-Ph
3-F-Ph
9.9
9.6
8.9
O
H
N
N
17h
17i
17j
NHCOCH2NH2
NHCOCH2NHCH3
NHCOCH2N(CH3)2
3-F-Ph
3-F-Ph
3-F-Ph
9.5
9.8
9.4
O
H
17ah
17ai
17aj
N
3-F-Ph
3-F-Ph
3-F-Ph
9.2
10.0
8.2
HN
17k
17l
17m
CONHC(@NH)NH2
NHCONH2
NHCONHCH3
3-F-Ph
3-F-Ph
3-F-Ph
9.2
9.7
9.4
OH
N
N
17n
17o
17p
NHCON(CH3)2
N(CH3)CONH2
NHCO2CH3
3-F-Ph
3-F-Ph
3-F-Ph
8.6
7.4
8.8
O
NH
17q
17r
17s
17t
NHCOCH3
3-F-Ph
3-F-Ph
3-F-Ph
3-F-Ph
9.9
8.8
10.0
9.1
21a
21b
21c
21d
NHCH2CH2OH
NHCONH2
NHCOCH2OH
NHCOCH3
3-F-Ph
3-F-Ph
3-F-Ph
Ph
9.8
9.7
9.6
9.5
N(CH3)COCH3
NHCOCH2OH
NHCOCH2OCH3
a
Affinities (pKi in Àlog M) were determined by radioligand binding with [3H] LSD in membranes prepared from cells engineered to recombinantly express human 5-HT6
receptors.

R. N. Harris III et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3436–3440
3439
gained affinity relative to the less substituted analogs 1–3. These
data again imply a deviation in binding interactions for the non-ba-
sic ligands, and that the new interaction involves a H-bond dona-
tion from the ligand head group to the receptor.
To gain insight into the binding results at the molecular level,
the binding of several analogs to h5-HT6 receptor point mutations
was examined. The results are shown in Table 3 and are tabulated
as change in binding pKi (DpKi) relative to wild type receptor pro-
tein. The agonist 5-HT and arylpiperazine SB-258585, a known
selective antagonist,15 are included as reference ligands. As noted
in Table 3, SB-258585 and tetralin amines 16d, 16j, and 17e all
experienced significant reduction in affinity with mutation
D106A, consistent with Asp106 being the anchoring point for basic
amine antagonists. Interestingly however, the magnitude of the
reduction for the tetralin amines is essentially a full order less than
that for the arylpiperazine SB-258585. This implies that the tetralin
amines may not depend solely on Asp106 for binding of the head
group. In contrast, the neutral polar head group analogs 17l and
21d (Table 3) experienced no significant decline in affinity with
mutation D106A indicating these analogs to be totally independent
of Asp106 for binding. Point mutations C110A, S193A, and T196A,
all mutations of polar residues that have been implicated in bind-
ing models by other investigators,11 had in this investigation min-
imal to no effect on binding. The one point mutation that produced
a significant effect with all ligands is F284A. Phe284 is located on
helix 6 opposite to TM3 Asp106 and in close sequence with
Trp281 and Phe285, all of which make up a region of the receptor
that is rich in hydrophobic aromatic residues. The data in Table 3
suggests that this hydrophobic pocket, and in particular Phe284,
is probably a critical common site for all 5-HT6 antagonists to bind
Figure 2. Graphics illustration of non-basic ligand 21d docked in the 5-HT6
receptor with new H-bond interactions at TM3 Thr103 and TM5 Ser185 highlighted.
at the top of the view for reference. Notably, the model reveals an
additional H-bond from TM5 Ser185 to the amide carbonyl of 21d
that occurs as a result of the positioning of the ligand to Thr103.
This additional interaction strengthens the binding of the head
group and serves to completely block access to the agonist binding
site at Asp106. Moreover, the model reveals that the ligand core
ring system does not significantly interact with receptor protein,
but instead serves primarily as a scaffold to bridge a specific dis-
tance across the interior allowing the pharmacophore extremities
to make contact points. This, along with dual binding sites for
the ligand polar head group, could explain why so many different
ring systems have been identified as active templates for 5-HT6
antagonists.8
Although rare, non-amine serotonin receptor ligands are not to-
tally unknown. Recently, Ladduwahetty et al.17 reported a series of
acylated and sulfonylated 4-phenethyl-piperidines as non-basic 5-
HT2A antagonists demonstrating that a basic amine is not a
requirement for 5-HT2A binding. While 5-HT6 is known to share
40–45% sequence homology with 5-HT2,18 the Asp106 residue for
forming a salt bridge is conserved in almost all aminergic recep-
tors. Whether a non-amine binding site in other aminergic recep-
tor proteins is conserved or not remains to be determined.
Nevertheless, the discovery of non-amine functional ligands for
both 5-HT6 and 5-HT2 brings the discovery of other such ligands
for related receptors into the realm of possibility, and has signifi-
cant implications from a safety standpoint for therapy areas that
target aminergic receptors. A major safety advantage of non-amine
ligands is their general tendency to have little to no affinity for
inhibiting the IKr potassium channel (hERG), a voltage gated ion
channel that is intimately involved in cardio rhythm. In fact, many
of the neutral ligands in Table 2 were found to be essentially de-
via aromatic ring
p-stacking. Hence, although the non-basic li-
gands, unlike the basic amines, bind independent of Asp106, both
ligand types still share a common point of interaction of pendant
ring with Phe284, and are therefore most likely oriented at the recep-
tor in a similar manner. The remaining question is: what receptor
residue accepts the H-bond from the non-basic head group?
Considering an orientation within the helix complex that is sim-
ilar for both basic amine and neutral ligands, it is reasonable to as-
sume that for the neutral ligands to competitively block the
receptor, the H-bond donation must be to a residue in helix 3 near
the residue with which the amine group of 5-HT interacts,16 that is,
Asp106. Modeling studies of 21d in the receptor site reveal only
one residue in helix 3 capable of fulfilling these requirements,
and that is Thr103. Figure 2 shows a graphics model of a view look-
ing down the interior of the helix complex with 21d docked in the
optimum orientation for H-bond donation to Thr103 and hydro-
phobic p-stacking of pendant ring with Phe284. The positive ioniz-
able binding site for basic amine ligands at TM3 Asp106 is shown
Table 3
Change in binding pKi from WT h5-HT6 to h5-HT6 amino acid point mutations for
selected compounds
h5-HT6 point mutationsa
(DpKi)
D106A
C110A
S193A
T196A
W281A
F284A
N288A
void of IKr channel affinity having IC50 values typically >50 lM.
5-HT
SB-258585
16d
16j
17e
À1.3
À2.4
À1.1
À1.5
À0.7
0
À0.5
0.5
0.3
0.4
0.4
0.3
0.4
À0.7
À0.3
0.1
À0.7
0.3
0.2
0.4
0.5
0.4
0.4
À0.5
À0.5
À2.0
À0.9
À0.5
À1.4
À2.0
À1.3
À1.3
À1.2
À1.7
À0.7
À1.5
À1.5
À0.5
À0.7
À0.7
À0.7
À0.2
À0.5
À0.4
In contrast to this, many of the analogs 16 and 17 that incorporate
amine functionality, which is believed to be a major contributor to
the hERG pharmacophore,19 were found to have IC50’s in the range
À0.4
0.1
0.5–5
ably good brain penetration and a CYP450 panel of IC50 values all
in excess of 15 M.
lM. Finally, a PK profile of acetamide 21d revealed reason-
17l
21d
À0.4
À0.4
À0.2
l
a
Amino acid abbreviations: D (aspartic acid), A (alanine), C (cysteine), S (serine),
In conclusion, a series of very potent 5-HT6 antagonists based
on the (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin molecular
template was prepared. N-acylated and N-sulfonylated derivatives
T (threonine), W (tryptophan), F (phenylalanine), N (asparagine). Affinities (pKi in
Àlog M) were determined by radioligand binding in membranes prepared from
cells engineered to recombinantly express human 5-HT6 receptors.

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R. N. Harris III et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3436–3440
4. Routledge, C.; Bromidge, S. M.; Moss, S. F.; Price, G. W.; Hirst, W.; Newman, H.;
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D. N. Br. J. Pharmacol. 2000, 130, 1606.
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of the series gave functionally active, non-basic analogs having
sub-nanomolar binding affinities. Based on SAR, receptor point
mutation studies, and molecular modeling, a novel binding orien-
tation for the non-basic antagonists was proposed that does not in-
volve an interaction with Asp106, but instead relies on H-bond
interactions of the polar head group with receptor residues
Thr103 and Ser185. These results introduce a new alternative bind-
ing model for the design of highly potent, non-basic 5-HT6 antag-
onists that have very little to no hERG liability.
Acknowledgement
8. For excellent reviews of 5-HT6 antagonists, see: (a) Liu, K. G.; Robichaud, A. J.
Drug Dev. Res. 2009, 70, 145; (b) Holenz, J.; Pauwels, P. J.; Diaz, J. L.; Merce, R.;
Codony, X.; Buschmann, H. Drug Discovery Today 2006, 11, 283; (c) Woolley, M.
L.; Marsden, C. A.; Fone, K. C. F. Curr. Drug Targets CNS Neurol Disord. 2004, 3, 59.
9. Bromidge, S. M. In Special Publication—Roy. Soc. Chem. 2001, 264, 101.
10. (a) Pullagurla, M. R.; Westkaemper, R. B.; Glennon, R. A. Bioorg. Med. Chem. Lett.
2004, 14, 4569; (b) Pullagurla, M. R.; Siripurapu, U.; Kolanos, R.; Bondarev, M.
L.; Dukat, M.; Setola, V.; Roth, B. L.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2005,
15, 5298; (c) Sikazwe, D.; Bondarev, M. L.; Dukat, M.; Rangisetty, J. B.; Roth, B.
L.; Glennon, R. A. J. Med. Chem. 2006, 49, 5217.
We are very grateful to Ken Brameld for providing the excellent
graphics for Figure 2.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.03.110.
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