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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