Journal of cancer research updates,
Journal Year:
2022,
Volume and Issue:
11, P. 70 - 77
Published: Oct. 27, 2022
Almost
40%
of
cancer
patients
have
neuropathic
pain
or
mixed
with
a
component,
which
can
be
intense,
debilitating,
and
challenging
to
treat.
New
studies
on
sigma
receptors
show
these
enigmatic
ligand-binding
protein
chaperones
may
helpful
drug
targets
for
new
pharmacologic
options
reduce
many
types
neuropathies,
including
chemotherapy-induced
peripheral
neuropathy
(CIPN)
other
cancer-related
syndromes.
Our
objective
was
review
the
literature,
preclinical
findings,
in
support
sigma-1
receptor
(S1R)
antagonists
reducing
sigma-2
(S2R)
agonists
neuroprotection.
The
mechanisms
behind
effects
are
not
yet
fully
elucidated.
role
S1R
treating
CIPN
appears
promising.
In
some
cases,
combination
therapy
an
opioid—which
is
true
analgesic—with
antagonist,
anti-hyperalgesic
anti-allodynic
agent,
has
been
proposed.
Of
interest,
but
well
studied
whether
might
effective
pre-existing
diabetic
neuropathy.
While
syndromes
occur
hematologic
cancers,
effective.
Sigma
being
actively
now
variety
conditions
ranging
from
Alzheimer’s
disease
Parkinson’s
as
pain.
International Journal of Molecular Sciences,
Journal Year:
2023,
Volume and Issue:
24(15), P. 12025 - 12025
Published: July 27, 2023
Sigma
(σ)
receptors
are
a
class
of
unique
proteins
with
two
subtypes:
the
sigma-1
(σ1)
receptor
which
is
situated
at
mitochondria-associated
endoplasmic
reticulum
(ER)
membrane
(MAM),
and
sigma-2
(σ2)
receptor,
located
in
ER-resident
membrane.
Increasing
evidence
indicates
involvement
both
σ1
σ2
pathogenesis
Alzheimer’s
disease
(AD),
thus
these
represent
potentially
effective
biomarkers
for
emerging
AD
therapies.
The
availability
optimal
radioligands
positron
emission
tomography
(PET)
neuroimaging
humans
will
provide
tools
to
monitor
progression
treatment
outcomes.
In
this
review,
we
first
summarize
significance
pathophysiology
highlight
therapeutic
strategies
related
receptors.
We
then
survey
potential
PET
radioligands,
an
emphasis
on
requirements
imaging
or
humans.
Finally,
discuss
current
challenges
development
receptors,
opportunities
elucidate
as
novel
early
diagnosis,
monitoring
drug
efficacy.
Journal of Medicinal Chemistry,
Journal Year:
2023,
Volume and Issue:
66(14), P. 9658 - 9683
Published: July 7, 2023
In
search
of
new
dual-acting
histamine
H3/sigma-1
receptor
ligands,
we
designed
a
series
compounds
structurally
based
on
highly
active
in
vivo
ligands
previously
studied
and
described
by
our
team.
However,
kept
mind
that
within
the
previous
series,
pair
closely
related
compounds,
KSK67
KSK68,
differing
only
piperazine/piperidine
moiety
structural
core
showed
significantly
different
affinity
at
sigma-1
receptors
(σ1Rs).
Therefore,
first
focused
an
in-depth
analysis
protonation
states
piperazine
piperidine
derivatives
compounds.
16
mainly
core,
selected
three
lead
structures
(3,
7,
12)
for
further
biological
evaluation.
Compound
12
broad
spectrum
analgesic
activity
both
nociceptive
neuropathic
pain
models
novel
molecular
mechanism.
ACS Pharmacology & Translational Science,
Journal Year:
2025,
Volume and Issue:
8(4), P. 951 - 977
Published: March 7, 2025
Cancer
ranks
among
the
top
triumvirate
leading
causes
of
human
deaths
worldwide.
The
pathological
mechanisms
are
notably
intricate,
demonstrating
proliferative
and
metastatic
capabilities,
which
complicate
therapeutic
interventions.
sigma-1
receptor
(σ1R)
plays
a
crucial
role
in
tumor
survival
migration,
while
sigma-2
(σ2R)
is
intimately
associated
with
proliferation.
This
review
encapsulated
investigation
concerning
σ1R
σ2R
neoplasms
rigorously
summarized
ligands
radio-ligands
development
their
applications,
such
as
antitumor
cell
proliferation
PET/SPECT
imaging
tumors.
A
comprehensive
classification
discussion
was
undertaken
regarding
chemical
structures
emphasized
possibility
dual/multitargeted
ligands.
Ultimately,
we
discussed
effects
chiral
pharmacological
characteristics
on
affinity
pharmacokinetic
features
vivo,
particularly
radiopharmaceuticals.
functions
beneficial
resource,
fostering
ligand
deployment
stimulating
generation
innovative
ideas
for
developing
Nature Communications,
Journal Year:
2025,
Volume and Issue:
16(1)
Published: March 13, 2025
Chronic
pain
and
opioid
overdose
deaths
highlight
the
need
for
non-addictive
analgesics
with
novel
mechanisms.
The
δ
receptor
(δOR)
is
a
promising
target,
as
it
lacks
respiratory
depression
associated
µ
(µOR)
agonists.
However,
early
δOR
full
agonists
caused
seizures,
limiting
their
clinical
use.
Partial
may
offer
more
controlled
activation
than
agonists,
but
development
has
been
hindered
by
uncertainty
regarding
molecular
mechanism
of
partial
agonism.
Here
we
show
that
C6-Quino,
bitopic
ligand
developed
through
structure-based
design,
acts
selective
agonist.
Functional
studies
reveal
C6-Quino
shows
differential
activity
at
G-protein
arrestin
pathways
interacts
sodium
binding
pocket,
confirmed
cryo-EM
analysis.
demonstrates
oral
activity,
analgesic
in
chronic
models
without
causing
δOR-related
seizures
µOR-related
adverse
effects
which
have
limited
usage
recent
times.
This
discovery
outlines
new
strategy
developing
δOR-targeted
provides
framework
optimizing
signaling
profiles
other
Class
A
GPCRs.
δ-Opioid
receptors
are
targets
management
reduced
side
effects.
Here,
authors
use
approach
to
design
characterize
agonist,
highlighting
its
potential
therapeutic
relevance.
Journal of Medicinal Chemistry,
Journal Year:
2023,
Volume and Issue:
66(18), P. 12840 - 12857
Published: Sept. 13, 2023
Novel
ligands
with
the
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
or
5,6-dimethoxyisoindoline
pharmacophore
were
designed
and
synthesized
for
evaluation
of
their
structure-activity
relationship
to
sigma-2
(σ2)
receptor
developed
as
suitable
PET
radioligands.
Compound
1
was
found
possess
nanomolar
affinity
(Ki(σ1)
=
2.57
nM)
σ2
receptor,
high
subtype
selectivity
(>2000-fold),
over
40
other
receptors
transporters.
Radioligand
[18F]1
prepared
radiochemical
yield
37-54%,
>
99%
purity,
molar
activity
107-189
GBq/μmol.
Biodistribution
blocking
studies
in
mice
micro-PET/CT
imaging
rats
indicated
excellent
binding
specificity
vivo.
Micro-PET/CT
U87MG
glioma
xenograft
model
demonstrated
clear
tumor
visualization
uptake
tumor-to-background
ratio.
Co-injection
CM398
(5
μmol/kg)
led
a
remarkable
reduction
(80%,
60-70
min),
indicating
specific
xenografts.
