Novel positive allosteric modulator of AMPA-receptors based on tricyclic scaffold

Article abstract of DOI:10.1016/j.mencom.2018.05.028

Molecular modeling, synthesis, and activity evaluation of a novel positive allosteric modulator of the AMPA receptor, 6-[4-methoxy-3-(1H-pyrazol-1-ylmethyl)benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1^3,11]tetradecane-4,8,12-trione, are pr

Full text of DOI:10.1016/j.mencom.2018.05.028

Mendeleev
Communications
Mendeleev Commun., 2018, 28, 311–313
Novel positive allosteric modulator of AMPA-receptors
based on tricyclic scaffold
Mstislav I. Lavrov,a,b Dmitry S. Karlov,a,b Vladimir A. Palyulin,*a,b Vladimir V. Grigoriev,b
Vladimir L. Zamoyski,b Galina E. Brkich,c Natalia V. Pyatigorskayac and Maxim E. Zapolskiyd
a Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 939 0290; e-mail: vap@qsar.chem.msu.ru
b Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka,
Moscow Region, Russian Federation
c I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russian Federation
d QM PHARMA LLC, Skolkovo Innovation Center, 143026 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2018.05.028
O
N
Molecular modeling, synthesis, and activity evaluation of a
novel positive allosteric modulator of the AMPA receptor,
6-[4-methoxy-3-(1H-pyrazol-1-ylmethyl)benzyl]-1,11-di-
methyl-3,6,9-triazatricyclo[7.3.1.13,11]tetradecane-4,8,12-trione,
are presented. The main point of the design was to fill the
interdomain cavity of GluA2 ligand binding domains based
on the cyclothiazide binding mode. Electrophysiological studies
showed high potentiation of the kainate-induced currents
(pECmax ~ 12).
Me
Me
N
N
O
O
OMe
N
N
pCEmax ~ 12
Glutamatergic system plays an essential role in the functioning
of the mammalian central nervous system (CNS).1 Two different
families of glutamate receptors, viz. ionotropic (ligand-gated ion
channels, iGluRs) and metabotropic (G-protein coupled) ones, are
widely distributed in the CNS.2 In turn, ionotropic glutamate
receptors are divided into three types based on their sensitivity
to the selective agonists: N-methyl-d-aspartic acid (NMDA-
receptors), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA receptors), and kainic acid (KA, kainate receptors).3
In recent years, a special interest has been attracted to positive
allosteric modulators (PAMs) of AMPA receptors. Their therapeutic
value has been the subject of deep discussions in reviews.4 As
compared to the direct AMPA receptor agonists, positive allosteric
modulators perform the fine-tuning of glutamatergic system in a
better way since they do not cause any effects in the absence of
the natural ligand in a synapse. In particular, in the case of direct
agonists, an overdose can cause the hyperstimulation of CNS
glutamatergic system and neurotoxicity leading to the uncontrolled
brain damage.5 In contrast, positive allosteric AMPA receptor
modulators have relatively few side effects in therapeutically
effective doses.6 Moreover, PAMs are neuroprotective against
lesions induced by NMDA agonists.7
The dysfunction of glutamatergic neurotransmission is a primary
reason of a number of neurological and psychiatric diseases.8
Enhancement of AMPA signals by allosteric modulators can
be useful in the treatment of neurological disorders such as
depression,9 schizophrenia,10 Parkinson’s disease,11 Alzheimer’s
disease,12 attention deficit/hyperactivity disorder, and mood
disorders.13 This therapeutic effect is associated, at least in part,
with the property of AMPA receptor PAMs to significantly
increase the expression of neurotrophic factors – nerve growth
factor and brain-derived neurotrophic factor,14 which, in turn,
is the most powerful mechanism of differentiation of neural stem
cells.
Earlier, we performed a series of molecular modeling studies
of various PAMs in complexes with the dimer of AMPA receptor
glutamate-binding domains, the synthesis of promising structures
and their biological tests.15–17 For the rational design of new
PAMs, a pharmacophore hypotheses were also suggested.18,19
As a result, we designed a new scaffold of general formula A
and a series of compounds was synthesized on its basis. In this
communication, we present 6-[4-methoxy-3-(1H-pyrazol-1-yl-
methyl)benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.13,11]-
tetradecane-4,8,12-trione 1 (Scheme 1) from this series which
exhibited the most significant activity as a positive allosteric
modulator of AMPA receptor.
O
Me
Me
N
N
O
O
N
R
A
The results of the docking study demonstrate the cyclothiazide-
like binding mode of compound 1 on the contact surface between
GluA2 ligand binding domains (flip form). The docking proce-
dure20 was carried out using Rosetta 3.5 (10000 launches of the
search algorithm, the best pose was selected). Captions were made
using VIDA 4.3.021 and Grapheme TK.22 Binding is maintained
by hydrogen bonds between the ligand and Ser518 (Figure 1).
In the synthesis of compound 1 (see Scheme 1), amine 5 was
prepared24,25 by N-alkylation of pyrazole with 3-chloromethyl-
4-methoxybenzaldehyde 2, transformation of aldehyde 3 into the
© 2018 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2018, 28, 311–313
180
160
140
120
100
80
NH2
CHO
CH=NOH
CHO
*
*
iii
i
ii
*
N
MeO
Cl
MeO
N
N
MeO
MeO
N
N
N
60
40
2
3 (83%)
5 (74%)
4 (93%)
20
O
0
Me
Me
Control –13 –12 –11 –10 –9
–8 –7 –6
Cl
O
log C
Figure 2 Results of in vitro study of compound 1 by the patch-clamp
technique. The vertical axis demonstrates the increase in kainate-induced
currents relative to the control (m±SD). Asterisks mark the reliable
differences from the control (p < 0.05).
N
N
Me
iv
N
O
O
O
N
N
O
Me
N
treatment with subsequent mechanical dissociation by Pasteur
pipettes.27 The transmembrane currents of individual nerve cells
were recorded by the local potential fixation method (patch-
clamp) in a whole-cell configuration using the EPC-9 device.
To obtain AMPA cell responses to mediator application, KA
in a concentration of 2×10–4 to 5×10–4 mol dm–3 dissolved in
physiological solution was used.
N
Cl
MeO
6
1 (76%)
Scheme 1 Reagents and conditions: i, pyrazole, 18-crown-6/C6H6/KOH/
H2O, 80°C; ii, NH2OH·HCl/pyridine/EtOH; iii, LiAlH4/THF; iv, amine 5,
K2CO3/MeCN, 60°C.
Figure 2 shows the final results for the entire range of
compound 1 concentrations (n = 22, the number of neurons): the
increase of the KA-induced AMPA receptor currents relative to
the control vs. the concentration of compound 1 (n = 3–7 experi-
ments for each column).
The data obtained demonstrate that compound 1 enhances
AMPA receptor responses in isolated Purkinje neurons in a wide
range of concentrations from 10–13 to 10–6 mol dm–3, while the
maximum potentiating effect is achieved at the concentration of
10–12 mol dm–3. The decay of potentiation at higher concentrations
possibly could be explained by the binding of compound 1 also
to one of the antagonist, negative modulator or channel blocker
binding sites despite the low affinity to it.
corresponding oxime 4 and its subsequent reduction. Synthesis of
bis(chloroacetamide) 6 was performed according to the published
procedures.26 Final stage involved the bis-alkylation of amine 5.
In vitro studies of compound 1 were conducted by electro-
physiological technique on freshly isolated Purkinje neurons from
the cerebellum of the rat brain slices (Wistar males, 12–15 days
old). Isolation of single neurons was facilitated by an enzymatic
(a)
In summary, it can be concluded that compound 1 exhibits
a pronounced effect characteristic of allosteric AMPA receptor
modulators. This gives a hope that after further optimization of
the structure it will be possible to develop a drug for the treatment
and prevention of neurodegenerative and neuropsychiatric diseases,
as well as for the improvement of memory and cognitive functions.
The authors are grateful to OpenEye Scientific Software for
kindly providing the academic license for molecular modeling
software.
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(b)
backbone
MET
517A
PRO
515A
SER
518A
PHE
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Received: 3rd November 2017; Com. 17/5396
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