Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
Pharmacological Research,
Год журнала:
2024,
Номер
208, С. 107363 - 107363
Опубликована: Авг. 23, 2024
G
protein-coupled
receptors
(GPCRs)
exist
within
a
landscape
of
interconvertible
conformational
states
and
in
dynamic
equilibrium
between
monomers
higher-order
oligomers,
both
influenced
by
ligand
binding.
Here,
we
show
that
homobivalent
formed
equal
chromenopyrazole
moieties
as
pharmacophores,
connected
14
methylene
units,
can
modulate
the
dynamics
cannabinoid
CB
Язык: Английский
Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and Its Modulation by Lysophosphatidylinositol in Human Breast Cancer Cells
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(2), С. 820 - 820
Опубликована: Янв. 19, 2025
2-arachnadoyl
glycerol
(2-AG)
is
one
of
the
most
common
endocannabinoid
molecules
with
anti-proliferative,
cytotoxic,
and
pro-proliferative
effects
on
different
types
tumors.
Typically,
it
induces
cell
death
via
cannabinoid
receptor
1/2
(CB1/CB2)-linked
ceramide
production.
In
breast
cancer,
counterbalanced
by
sphingosine-1-phosphate,
thus
mechanisms
2-AG
influence
proliferation
are
poorly
understood.
We
evaluated
mechanism
anti-proliferative
action
lysophaosphatidylinositol
(LPI)
in
six
human
cancer
lines
tumor
degree
(MCF-10A,
MCF-7,
BT-474,
BT-20,
SK-BR-3,
MDA-MB-231)
using
resazurin
test,
inhibitor,
blocker,
anti-oxidant
analysis,
siRNA
interference.
To
avoid
acyl
migration
2-AG,
we
replaced
analog
2-arachidonoyl-1,3-difluoropropanol
(2-ADFP)
newly
synthesized
us.
Using
a
molecular
docking
approach,
showed
that
at
CB2
receptor,
2-ADFP
were
very
close
to
each
other.
However,
demonstrated
stronger
affinity
towards
CB1
antagonist-bound
conformation.
was
all
tested.
The
toxicity
enhanced
LPI.
activity
reduced
or
prevented
vanilloid
1
(TRPV1)
blockers,
inositol
triphosphate
CREB,
cyclooxygenase
2
addition.
Together
literature
data,
these
results
indicate
CB2-
TRPV1-dependent
COX-2
induction
concomitant
oxidized
molecule’s
metabolites.
Язык: Английский
Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors
Pharmacology & Therapeutics,
Год журнала:
2025,
Номер
unknown, С. 108802 - 108802
Опубликована: Янв. 1, 2025
Язык: Английский
The complexity of G protein‐coupled receptor (GPCR) modulation and signalling
British Journal of Pharmacology,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 9, 2025
Язык: Английский
Homodimerization of CB2cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Май 11, 2024
ABSTRACT
G
protein-coupled
receptors
(GPCRs)
exist
within
a
landscape
of
interconvertible
conformational
states
and
in
dynamic
equilibrium
between
monomers
higher-order
oligomers,
both
influenced
by
ligand
binding.
Here,
we
have
shown
that
homobivalent
formed
equal
chromenopyrazole
moieties
as
pharmacophores,
connected
14
methylene
units,
can
modulate
the
dynamics
cannabinoid
CB
2
receptor
(CB
R)
homodimerization
simultaneously
binding
protomers
R-CB
R
homodimer.
Computational
pharmacological
experimentals
showed
one
pharmacophores
binds
to
orthosteric
site
protomer,
other
pharmacophore
membrane-oriented
pocket
transmembranes
1
7
partner
protomer.
This
provides
unique
properties,
such
increased
potency
i
recruitment
β-arrestin.
Thus,
modulating
dimerization
dynamics,
it
may
be
possible
fine-tune
activity
with
potentially
improved
therapeutic
outcomes.
HIGHLIGHTS
A
(PM369)
modulates
PM369
protomer
complementary,
membrane-facing,
triggers
via
TM
1/7
interface
properties
potentiates
signaling,
β-arrestin
These
results
highlight
new
approaches
control
GPCR
signaling
GRAPHICAL
Язык: Английский
The Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and its Modulation by Lysophosphatidylino-sitol in Human Breast Cancer Cells
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 1, 2024
Abstract
2-arachnadoyl
glycerol
(2-AG)
is
one
of
the
most
common
endocannabinoid
molecules
with
antiproliferative,
cytotoxic
and
pro-proliferative
effects
on
different
types
tumors.
Typically,
it
induces
cell
death
via
CB1/CB2-linked
ceramide
production.
In
breast
cancer,
counterbalanced
by
sphingosine-1-phosphate,
thus
mechanisms
2-AG
influence
proliferation
are
poorly
understood.
this
paper,
we
evaluated
mechanism
induction
LPI
in
6
human
cancer
lines
tumor
degree
using
a
novel
analog,
2-arachidonoyl-difluoropropanol
(2-ADFP).
2-ADFP
induced
CB2
TRPV1-dependent
COX-2
oxidized
metabolites
The
activity
was
enhanced
LPI.
Язык: Английский
Design of Small Non-Peptidic Ligands That Alter Heteromerization between Cannabinoid CB1 and Serotonin 5HT2A Receptors
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 26, 2024
Activation
of
cannabinoid
CB1
receptors
(CB1R)
by
agonists
induces
analgesia
but
also
cognitive
impairment
through
the
heteromer
formed
between
CB1R
and
serotonin
5HT2A
receptor
(5HT2AR).
This
side
effect
poses
a
serious
drawback
in
therapeutic
use
cannabis
for
pain
alleviation.
Peptides
designed
from
transmembrane
helices
CB1R,
which
are
predicted
to
bind
5HT2AR
alter
stability
CB1R-5HT2AR
heteromer,
have
been
shown
avert
agonist-induced
while
preserving
analgesia.
Using
these
peptides
as
templates,
we
now
nonpeptidic
small
molecules
that
prevent
heteromerization
bimolecular
fluorescence
complementation
assays
heteromerization-dependent
allosteric
modulations
cell
signaling
experiments.
These
results
provide
proof-of-principle
design
optimized
ligand-based
disruptors
opening
new
perspectives
vivo
studies.
Язык: Английский