Journal of Medicinal Chemistry,
Год журнала:
2023,
Номер
66(17), С. 12499 - 12519
Опубликована: Авг. 22, 2023
The
synthesis
and
pharmacological
activity
of
a
new
series
isoxazolylpyrimidines
as
sigma-2
receptor
(σ2R)
ligands
are
reported.
Modification
hit
retrieved
in
an
HTS
campaign
allowed
the
identification
compound
WLB-89462
(20c)
with
good
σ2R
affinity
(Ki
=
13
nM)
high
selectivity
vs
both
σ1R
1777
general
panel
180
targets.
It
represents
one
first
drug-like
properties,
linked
to
physicochemical
ADMET
profile
(good
solubility,
no
CYP
inhibition,
metabolic
stability,
permeability,
brain
penetration,
oral
exposure
rodents).
Compound
20c
shows
neuroprotective
vitro
improves
short-term
memory
impairment
induced
by
hippocampal
injection
amyloid
β
peptide
rats.
Together
promising
effects
chronic
models
where
is
currently
being
evaluated,
these
results
pave
way
toward
its
clinical
development
agent.
Journal of Medicinal Chemistry,
Год журнала:
2022,
Номер
65(8), С. 6261 - 6272
Опубликована: Апрель 11, 2022
In
this
study,
a
panel
of
46
compounds
containing
five
different
scaffolds
known
to
have
high
σ2
receptor
affinity
were
screened.
6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline
[(±)-7]
(Ki
for
σ1
=
48.4
±
7.7
nM,
and
Ki
0.59
0.02
nM)
its
desmethyl
analogue,
(±)-8
108
35
4.92
nM),
showed
excellent
binding
subtype
selectivity
receptors.
vitro
cell
indicated
that
[11C]-(±)-7
[11C]-(±)-8
was
dependent
on
TMEM97
protein
expression.
PET
studies,
the
peak
brain
uptake
(8.28
2.52%ID/cc)
higher
than
(4.25
0.97%ID/cc)
with
specific
distribution
in
cortex
hypothalamus.
Brain
or
tissue
selectively
inhibited
by
ligands
affinities.
The
results
suggest
can
be
used
as
radiotracer
imaging
function
receptors
central
nervous
system
disorders.
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(4), С. 3417 - 3417
Опубликована: Фев. 8, 2023
Age-related
macular
degeneration
(AMD)
is
a
blinding
disease
characterised
by
dysfunction
of
the
retinal
pigmented
epithelium
(RPE)
which
culminates
in
disruption
or
loss
neurosensory
retina.
Genome-wide
association
studies
have
identified
>60
genetic
risk
factors
for
AMD;
however,
expression
profile
and
functional
role
many
these
genes
remain
elusive
human
RPE.
To
facilitate
AMD-associated
genes,
we
developed
RPE
model
with
integrated
CRISPR
interference
(CRISPRi)
gene
repression
generating
stable
ARPE19
cell
line
expressing
dCas9-KRAB.
We
performed
transcriptomic
analysis
retina
to
prioritise
selected
TMEM97
as
candidate
knockdown
study.
Using
specific
sgRNAs,
showed
that
reduced
reactive
oxygen
species
(ROS)
levels
exerted
protective
effect
against
oxidative
stress-induced
death.
This
work
provides
first
study
supports
potential
AMD
pathobiology.
Our
highlights
using
CRISPRi
genetics,
platform
generated
here
provided
useful
vitro
tool
genes.
Pain,
Год журнала:
2020,
Номер
162(4), С. 1163 - 1175
Опубликована: Окт. 2, 2020
Chronic
complications
of
traumatic
brain
injury
represent
one
the
greatest
financial
burdens
and
sources
suffering
in
society
today.
A
substantial
number
these
patients
suffer
from
posttraumatic
headache
(PTH),
which
is
typically
associated
with
tactile
allodynia.
Unfortunately,
this
phenomenon
has
been
understudied,
large
part
because
lack
well-characterized
laboratory
animal
models.
We
have
addressed
gap
field
by
characterizing
sensory
profile
2
nonpenetrating
models
PTH.
show
that
multimodal
injury,
administered
a
jet-flow
overpressure
chamber
delivers
severe
compressive
impulse
accompanied
variable
shock
front
acceleration-deceleration
insult,
produces
long-term
hypersensitivity
widespread
sensitization.
These
are
phenotypes
reminiscent
PTH
patients,
both
cephalic
extracephalic
regions.
By
contrast,
closed
head
induces
only
transient
hypersensitivity,
no
consequences.
Both
more
phenotype
repetitive
daily
for
3
days,
compared
either
1
or
successive
injuries
single
day,
providing
new
insight
into
patterns
may
place
at
greater
risk
developing
After
recovery
mice
subjected
to
demonstrate
persistent
established
migraine
triggers,
including
calcitonin
gene-related
peptide
sodium
nitroprusside,
nitric
oxide
donor.
Our
results
offer
tools
studying
preclinical
support
pathophysiologic
role
condition.
CNS Neuroscience & Therapeutics,
Год журнала:
2020,
Номер
26(6), С. 616 - 627
Опубликована: Март 10, 2020
Abstract
Traumatic
brain
injury
(TBI)
causes
death
and
disability
in
the
United
States
around
world.
The
traumatic
insult
mechanical
of
primary
cellular
death.
While
a
comprehensive
pathological
mechanism
TBI
is
still
lacking,
focus
research
concentrated
on
understanding
pathophysiology
developing
suitable
therapeutic
approaches.
Given
complexities
involving
interconnected
immunologic,
inflammatory,
neurological
cascades
occurring
after
TBI,
therapies
directed
to
single
fail
clinical
trials.
This
has
led
development
paradigm
combination
approach
against
TBI.
there
are
no
drugs
available
for
treatment
stem
cell
therapy
shown
promising
results
preclinical
studies.
But,
success
depends
survival
cells,
which
limited
by
several
factors
including
route
administration,
health
administered
inflammatory
microenvironment
injured
brain.
Reducing
inflammation
prior
administration
may
provide
better
outcome
following
review
focused
different
approaches
present
status
eNeuro,
Год журнала:
2024,
Номер
11(7), С. ENEURO.0488 - 23.2024
Опубликована: Июнь 12, 2024
Previous
studies
have
shown
that
ligands
bind
to
sigma-2
receptor/TMEM97
(s
2
R/TMEM97),
a
transmembrane
protein,
anxiolytic/antidepressant-like
properties
and
relieve
neuropathic
pain-like
effects
in
rodents.
Despite
medical
interest
s
R/TMEM97,
little
affective
pain
behavioral
characterization
has
been
done
using
transgenic
mice,
which
limits
the
development
of
R/TMEM97
as
viable
therapeutic
target.
Using
wild-type
(WT)
global
Tmem97
knock-out
(KO)
we
sought
identify
contribution
modulating
behaviors
battery
assays,
including
open
field,
light/dark
preference,
elevated
plus
maze,
forced
swim
test,
tail
suspension
mechanical
sensitivity
tests.
Our
results
demonstrate
female
KO
mice
show
less
anxiety-like
depressive-like
preference
tests
but
not
an
at
baseline.
We
next
performed
spared
nerve
injury
WT
assess
role
pain-induced
anxiety
depression.
developed
prolonged
phenotype
when
tested
10
weeks
after
females.
plays
naive
animals
with
significant
change
presence
mice.
Overall,
these
data
could
be
target
alleviate
comorbidities
disorders.
