Pyrano[2,3,4-cd]indole as a Scaffold for Selective Nonbasic 5-HT6R Ligands

Article abstract of DOI:10.1021/acsmedchemlett.6b00482

In this letter, we report the synthesis of a pyrano[2,3,4-cd]indole chemical scaffold designed through a tandem bioisostere generation/virtual screening protocol in search of 5-HT₆R ligands. The discovered chemical scaffold resulted in the design of highly active basic and nonbasic 5-HT₆R ligands (5-HT₆R K_i = 1 nM for basic compound 6b and 5-HT₆R K_i = 4 nM for its neutral analog 7b). Additionally, molecular modeling suggested that the hydroxyl group of nonbasic ligands 7a-7d forms hydrogen bonds with aspartic acid D^3×32 or D^7.36×35

Full text of DOI:10.1021/acsmedchemlett.6b00482

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Letter
A pyrano[2,3,4-cd]indole as a scaffold for selective non-basic 5-HT6R ligands
Jakub Staro#, Stefan Mordalski, Dawid Warszycki, Grzegorz
Sata#a, Adam S. Hogendorf, and Andrzej J. Bojarski
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00482 • Publication Date (Web): 27 Mar 2017
Downloaded from http://pubs.acs.org on March 28, 2017
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A pyrano[2,3,4-cd]indole as a scaffold for selective non-basic
5-HT6R ligands
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Jakub Starońa†, Stefan Mordalskia, Dawid Warszyckia, Grzegorz Satałaa, Adam Hogendorfa, Andrzej J.
Bojarskia
a Institute of Pharmacology, Polish Academy of Sciences, 31ꢀ343 Kraków, 12 Smętna Street, Poland.
ABSTRACT: In this paper, we report the synthesis of a pyrano[2,3,4ꢀcd]indole chemical scaffold designed through a tandem bioisostere
generation/virtual screening protocol in search of 5ꢀHT6R ligands. The discovered chemical scaffold resulted in the design of highly active
basic and nonꢀbasic 5ꢀHT6R ligands (5ꢀHT6R Ki = 1 nM for basic compound 6b and 5ꢀHT6R Ki = 4 nM for its neutral analog 7b). Addiꢀ
tionally, molecular modeling suggested that the hydroxyl group of nonꢀbasic ligands 7a–7d forms hydrogen bonds with aspartic acid D3x32
or D7.36x35
.
KEYWORDS: Serotonin, 5-HT6, non-basic, molecular modeling, bioisosteres, virtual screening
Supporting Information Placeholder
The 5ꢀHydroxytryptanime receptor 6 (5ꢀHT6R) is one of fourꢀ
teen identified serotonin receptors belonging to the Class A Gꢀ
protein coupled receptors (GPCRs) and is positively coupled to
adenylate cyclase.1,2 It has been found that this receptor is distribꢀ
uted almost exclusively in areas of the central nervous system
(CNS), which suggests that its ligands are unlikely to cause undeꢀ
sirable peripheral side effects.3 In situ hybridisation studies of the
5ꢀHT6 receptor in rat brains using mRNA showed a major locaꢀ
tion in the projection areas of 5ꢀHT neurons, especially in the
structures essential for cognitive processes.4 The location of 5ꢀ
HT6R clearly suggests application of its ligands as a procognitive
drugs, which was confirmed in animal models.5 Additionally,
recent findings showed that 5ꢀHT6R is involved in the developꢀ
ment of neural circuits, including neuronal migration and neurite
growth.6,7 As it was shown, blockade of 5ꢀHT6R is a promising
new therapeutic perspective in the treatment of cognitive decline
in patients with schizophrenia.7
et al.15 were tested against 55 therapeutic targets and achieved
5000ꢀ to >50000ꢀfold selectivity towards 5ꢀHT6R. Van Loevezijn
et al.16 profiled their ligands in a panel of 86 receptors, ion chanꢀ
nels, transporters and 27 enzymes. The only offꢀtarget for which
weak affinities were observed was the translocator protein and 5ꢀ
HT2BR.
Our initial attempt was to design a novel 5ꢀHT6R ligands using
an automated bioisostere generation from the Pipeline Pilot softꢀ
ware17. As a basis for the bioisostere generation we utilized 10
structurally diverse, highly active 5ꢀHT6R ligands (parent strucꢀ
tures) that were manually selected from 5ꢀHT6R ligands stored in
the ChEMBL (version 13) database (see Supplementary Inforꢀ
mation, page 2).18
Each of these chemical entities was processed using the Breed
module of Pipeline Pilot,17 which resulted in 313 bioisosteres that
were subsequently visually inspected in terms of novelty and
synthetic accessibility (for selected compounds and information
about their synthesis see Supplementary Information, page 3).
Consequently, one bioisostere (6a) was selected for further evaluꢀ
ation, that emerged from reduction of the ring size together with
the aromatization of a parent compound A (Figure 1). Here, we
present the synthesis of a new pyrano[2,3,4ꢀcd]indole scaffold
that allowed us to obtain highly active basic and nonꢀbasic 5ꢀ
HT6R ligands.
So far, no selective 5ꢀHT6R ligand is used in the therapy, howꢀ
ever several compounds (all selective antagonists of 5ꢀHT6R) that
are currently under phase II or phase III clinical trials for the
treatment of moderate Alzheimer disease (e.g.: Idalopirdine –
Lundbeck; SUVNꢀ502 – Suven Life Sciences) and for amplifying
the effects of antipsychotic drugs (e.g.: AVNꢀ211 – Avineuro
Pharm. Inc., RVTꢀ101 – Axovant) indicated promising results.8
One major drawback of basic 5ꢀHT6R ligands is their possible
affinity towards hERG, because they fulfil the hERG pharmacoꢀ
phore model.9 Although there are examples of nonꢀbasic hERG
ligands,10 compounds devoid of a basic nitrogen atom are much
less likely to exhibit this kind of activity. Until recently, it was
believed that only a compound with a basic nitrogen atom could
be an orthosteric ligand of an aminergic GPCR. The validity of
this statement was widely acclaimed and independently supported
in numerous studies.11–14 However, the recent emergence of the
nonꢀbasic ligands has somehow shifted the paradigm of medicinal
chemistry.
N
N
O
O
O
N
N
X
S
O
S
O
O
O
tricyclic scaffold
A
6a
Figure 1. A general formula of a tricyclic scaffold (X = heteroaꢀ
tom), together with bioisosteric substitution ( ring size reduction
and aromatization) of the parent compound A.
A very important feature of the nonꢀbasic 5ꢀHT6R ligands is
their extreme selectivity. Compounds developed by Ivachtchenko
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Tricyclic scaffolds containing an indole moiety, as described by
All attempts to reduce the nitrile group to an amine were unꢀ
1
2
3
4
5
6
7
8
a presented general formula (Figure 1), have been barely explored
in medicinal chemistry. Only two groups of compounds containꢀ
ing a nitrogen atom can be found: pyrrolo[4,3,2ꢀde]quinolines
reported by Balczewski et al.,19 and marine alkaloids—
ammosamides resynthesized by Takayama et al.20 Ammosamides
present significant cytotoxicity against human colon adenocarciꢀ
noma and moderately inhibit human quinine reductase II. To date,
successful, and only after substitution of the indole nitrogen with
sulfonyl chlorides (compounds 4a–4d) was reduction with
DIBALꢀH possible, which afforded aldehydes 5a–5d.
Reductive amination or reduction of the obtained aldehydes reꢀ
sulted in the final products (6a–6c, 7a–7d).
Evaluation of the binding affinities of the synthesized comꢀ
pounds at four serotonin (5ꢀHT1A, 5ꢀHT2A, 5ꢀHT6, 5ꢀHT7) and
dopamine D2 receptors using in vitro radioligand displacement
revealed that all of the synthesized compounds (except 4b and 5b)
were potent 5ꢀHT6R ligands ( Ki = 1–52 nM, Table 1). The basic
derivatives (6a–6c) were generally 4ꢀ to 7ꢀfold more active than
their neutral analogs (7a–7d). Compounds possessing the 1ꢀ
naphthylsulfonyl moiety (6b, 7b, 7d) exhibited 2ꢀ to 9ꢀfold higher
affinity for 5ꢀHT6R than the benzenesulfonyl derivatives (6a, 6c,
7a, 7c), with 6b being the highest affinity ligand with 5ꢀHT6R Ki
= 1 nM. Introduction of a methyl group at C3 position of the
pyrano[2,3,4ꢀcd]indole (compounds 7c and 7d) resulted in 2ꢀ to 5ꢀ
fold less active compounds than compounds without methyl group
(7a and 7b). Analog 4b containing nitrile group was found to
possess low affinity for 5ꢀHT6R (266 nM), whereas analog 5b
with carbonyl group was 3ꢀfold less active (Ki = 755 nM).
there is only one analog containing
a
sulfur atom—
chuangxinmycin, a potent and selective inhibitor of bacterial
tryptophanyl tRNA synthetase.21 Surprisingly, no structures conꢀ
taining oxygen in the 6ꢀmembered ring have been reported to
date.
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The synthesis of the designed heterocyclic scaffold was
planned as an intramolecular condensation of a carbonyl with the
alpha carbon of a nitrile group.
The first step of the synthesis involved the addition of a chloroꢀ
acetonitrile to a 4ꢀhydroxyindole that resulted in 1 (Scheme 1).
Subsequent formylation was performed using DMF with NCS and
PPh3 as a formylating agent because of an unsuccessful standard
VilsmeyerꢀHaack reaction. Similarly, acetylation of 1 using Vilsꢀ
meyerꢀHaack conditions resulted in a mixture of unidentified
products. Finally, the utilization of diethylaluminium chloride
combined with acetyl chloride afforded the acetylated product
(2b) in high yield. The obtained intermediates (2a, 2b) were
cyclised in DMF with K2CO3 at 150 °C; however, the cyclisation
of 2b required much longer time compared to 2a (20 min vs. 4
hours).
Neutral analogs possessing a hydroxyl group exhibited much
greater selectivity towards other receptors, than their basic counꢀ
terparts, despite lower affinity for 5ꢀHT6R. Additionally, their
functional antagonist activity was retained though they lost the
ability to form a charge reinforced hydrogen bond with aspartic
acid D3x32 (in GPCRdb notation22), which was evidenced by the
value of Kb = 16 nM for 7a.
The binding mode of the synthesized compounds was investiꢀ
gated with docking experiments to the homology models of 5ꢀ
HT6R (see Supplementary Information). Both the basic and nonꢀ
Scheme 1. Synthesis of designed bioisosteres.
N
basic analogs exhibited very consistent binding modes (Figure 2),
H
O
O
23
overlapping with the previously reported data:
the peripheral
N
DMF, PPh3
NCS, THF
aromatic group formed stacking interactions with phenylalanines
F6x51 and F6x52, and the sulfonyl group of the ligands formed a
hydrogen bond with N6x55, in line with the mutagenetic data.24 In
addition, a protonated nitrogen atom of the basic analogs formed a
chargeꢀassisted hydrogen bond with D3x32, exhibiting the classical
binding mode for the basic compounds.25 The hydroxyl group
formed hydrogen bonds either with aspartic acid D3x32, D7.36x35 or
tyrosine Y7.43x42; however, the hydrogen bond with D7.36x35 was
the most populated.
N
H
OH
O
2a
ClCH2CN
N
Cs2CO3, acetone
N
H
N
H
1
O
O
AcCl
Et2AlCl, DCM
N
H
2b
N
N
R1
R1
The results of molecular modeling suggested that the polar inꢀ
teraction of the basic amine group might be replaced with the
interaction with another polar moiety (e.g., hydroxyl), and the in
vitro tests confirmed that such a substitution did not cause a sigꢀ
nificant drop of affinity and functional activity. Although nitrile
and carbonyl groups can form hydrogen bonds,26 the nitrile moieꢀ
ty pointed outside of the binding pocket preventing it from formꢀ
ing any interaction. In the case of the carbonyl, the hydrogen bond
was formed with a backbone nitrogen of leucine 182 located in
the extracellular loop 2. Such an interaction is very weak; neverꢀ
theless, the carbonyl derivative 5b exhibited 3ꢀfold higher affinity
than nitrile derivative 4b.
O
O
K2CO3
DMF
ArSO2Cl
K2CO3, ACN
N
N
H
S
O
Ar
3a R1 = H
3b R1 = Me
O
4a R1 = H, Ar = Ph
4b R1 = H, Ar = 1-naphthyl
4c R1 = Me, Ar = Ph
R2
4d R1 = Me, Ar = 1-naphthyl
R1
O
R32NH HCl
N
NaBH3CN
MeOH
H
O
O
S
Ar
R1
O
O
6a R1 = H, R2 = CH2N(Me)2, Ar = Ph
6b R1 = H, R2 = CH2N(Me)2, Ar = 1-naphthyl
6c R1 = H, R2 = CH2N(Et)2, Ar = Ph
DIBAL-H
DCM
N
R2
S
O
Ar
O
R1
5a R1 = H, Ar = Ph
O
5b R1 = H, Ar = 1-naphthyl
5c R1 = Me, Ar = Ph
NaBH4
MeOH
5d R1 = Me, Ar = 1-naphthyl
N
S
O
Ar
O
7a R1 = H, R2 = CH2OH, Ar = Ph
7b R1 = H, R2 = CH2OH, Ar = 1-naphthyl
7c R1 = Me, R2 = CH2OH, Ar = Ph
7d R1 = Me, R2 = CH2OH, Ar = 1-naphthyl
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Figure 2. Representative LꢀR virtual complexes of (A) 6b (5ꢀHT6R Ki = 1 nM, green) and 7b (5ꢀHT6R Ki = 4 nM, orange), and (B) 4b (5ꢀ
HT6R Ki = 266 nM, green) and 5b (5ꢀHT6R Ki = 755 nM, blue) with a homology model of 5ꢀHT6R. The protonated nitrogen atom of 6b
formed a chargeꢀassisted hydrogen bond with D3x32, and the hydroxyl group of 7b formed a hydrogen bond with D7.36x35. The carbonyl
oxygen of 4b formed a hydrogen bond with the backbone nitrogen of leucine L182. Sulfonyl groups of every compound formed hydrogen
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bonds with asparagine N6x55, whereas the peripheral aromatic rings (naphthalene) were placed between phenylalanines F6x51 and F6x52
forming stacking interactions. Yellow dotted lines indicate hydrogen bonds, whereas blue dotted lines indicate aromatic interactions.
,
Table 1. Structure and in vitro activity data of compounds 4b, 5b, 6a–c and 7a–d.
Ki [nM]a
Cmpd.
R1
R2
Ar
5ꢀHT6
755
5ꢀHT1A
> 10 000
> 10 000
5ꢀHT2A
n.d.
5ꢀHT7
D2
H
H
CN
1ꢀnaphthyl
1ꢀnaphthyl
> 10 000
> 10 000
> 10 000
5 162
4b
5b
CHO
266
n.d.
5
H
CH2N(Me)2
Ph
> 10 000
65
3 692
6 698
6a
Kb = 1.5 ± 0.5b
H
H
CH2N(Me)2
CH2N(Et)2
1ꢀnaphthyl
Ph
1
5 967
489
438
1 489
4 351
6b
6c
28
> 10 000
1 703
> 10 000
36
Kb = 16 ± 3b
4
H
CH2OH
Ph
> 10 000
> 10 000
> 10 000
> 10 000
7a
H
CH2OH
CH2OH
CH2OH
1ꢀnaphthyl
Ph
n.d.
> 10 000
> 10 000
> 10 000
> 10 000
> 10 000
> 10 000
4 287
7b
7c
7d
Me
Me
52
20
> 10 000
> 10 000
> 10 000
> 10 000
1ꢀnaphthyl
a Binding affinity, Ki, expressed as the average of at least two independent experiments; the maximum S.D. did not exceed 32% (see
b
Supplementary Information, page 6); full antagonist, Kb [nM] expressing the functional activity as the average of at least three indeꢀ
pendent experiments; n.d. – not determined. Affinity of the reference drugs: 5ꢀHT6R and 5ꢀHT2AR, Olanzapine – Ki = 10.7 ± 2.1 nM
and Ki = 6.2 ± 0.9 nM, respectively; 5ꢀHT1AR, Buspirone – Ki = 34.3 ± 4.2 nM; 5ꢀHT7R, Clozapine – Ki = 45.5 ± 5.1 nM; D2R,
Ziprasidone – Ki = 2.1 ± 0.3 nM.
The presented chemical scaffold of pyrano[2,3,4ꢀcd]indole is
unique, as no similar compounds have been reported in the literaꢀ
ture. The addition of an aromaticꢀsulfonyl moiety at the indole
nitrogen afforded highly active basic and neutral 5ꢀHT6R ligands.
Additionally, the nitrile group of compounds 3a and 3b allows
them to be utilized in click chemistry, thus providing a valuable
building block for the synthesis of biologically active compounds.
In addition, the compound 3a exhibited strong green fluorescence,
with a maximum emission of 520 nm (see Supplementary Inforꢀ
mation), which creates the possibility to use it as a building block
for fluorescent markers.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
†Tel.: +48 12 6623320, email: staron@if-pan.krakow.pl
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the betaꢀadrenergic receptor have different roles in receptor
function. J .Biol. Chem. 1988, 263 (21), 10267–10271.
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M.; Mitkin, O. D.; Tkachenko, S. E.; Okun, I. M. Synthesis and
Structure−Activity Relationship (SAR) of (5,7ꢀ Disubstituted 3ꢀ
phenylsulfonylꢀpyrazolo[1,5ꢀa]pyrimidinꢀ2ꢀyl)ꢀ methylamines
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Author Contributions
9
J.S. designed and synthesized compounds, S.M. performed the
docking to the 5ꢀHT6R model, D.W. performed the virtual screenꢀ
ing protocol, G.S. performed the in vitro tests, A.H. performed the
spectral analysis of compounds. J.S. and A.J.B. wrote the paper
with input from coauthors.
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ACKNOWLEDGMENT
The study was partially supported by the grant OPUS
2014/13/B/NZ7/02210 from the Polish National Science Centre
and grant PBS3/B7/20/2015 from the Polish National Centre for
Research and Development.
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5ꢀHT, 5ꢀhydroxytryptamine; 5ꢀHT6R, 5ꢀhydroxytryptamine reꢀ
ceptor 6; mRNA, messanger RNA; GPCR, Gꢀprotein coupled
receptor; hERG, human Ether-à-go-goꢀRelated Gene; DMF,
dimethylformamide; NCS, Nꢀchlorosuccimide; PPh3, triꢀ
phenylphosphine; DIBALꢀH, diisobutylaluminium hydride; D2,
dopamine receptor 2; GPCRdb, Gꢀ protein coupled receptor dataꢀ
base, S.D., standard deviation.
a largeꢀscale
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