bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 20, 2024
Abstract
The
mu-opioid
receptor
(MOR)
is
a
major
target
for
the
treatment
of
pain.
However,
opioids
are
prone
to
side
effects
which
limit
their
effectiveness
as
analgesics
and
can
lead
opioid
use
disorders
or,
even,
lethal
overdose.
systemic
administration
agonists
makes
it
both
very
difficult
decipher
underlying
circuit
mechanisms
action
drug
specific
subpopulations
isolate
therapeutic
from
adverse
effects.
Here
we
design,
synthesize,
characterize
reversibly
photoswitchable
morphinan
agonist
termed
“azo-morphine-3”
(
AM-3
)
interconverts
low
high
efficacy
in
response
different
wavelengths
light
enable
optical
control
MOR
signaling.
Cryo-EM
structures
“
trans
”
cis
states
bound
reveal
distinct
binding
modes
azobenzene
moiety,
each
inducing
unique
structural
dynamics,
providing
insight
into
molecular
basis
efficacy.
In
mice,
drives
reversible
repeatable
anti-nociception
with
reduced
effect
profile
owing
its
restriction
periphery
ability
be
locally
activated
at
site
Medicinal Research Reviews,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 3, 2025
ABSTRACT
Adrenoceptors
(ARs)
play
a
vital
role
in
various
physiological
processes
and
are
key
therapeutic
targets.
The
advent
of
optical
control
techniques,
including
optogenetics
photopharmacology,
offers
the
potential
to
modulate
AR
signaling
with
precise
temporal
spatial
resolution.
In
this
review,
we
summarize
latest
advancements
signaling,
encompassing
optogenetics,
photocaged
compounds,
photoswitchable
compounds.
We
also
discuss
limitations
current
tools
provide
an
outlook
on
next
generation
optogenetic
photopharmacological
tools.
These
emerging
technologies
not
only
enhance
our
understanding
but
pave
way
for
developments.
Medicinal Research Reviews,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 26, 2025
ABSTRACT
As
the
most
extensively
studied
photoswitch
in
photopharmacology,
azobenzene
has
precision
instrumental
photoregulation
of
physiological
processes
across
various
animal
models.
Currently,
it
exhibits
greatest
clinical
potential
for
photosensitive
retinal
restoration,
capable
inducing
long‐term
therapeutic
effects
following
intravitreal
injection,
without
need
foreign
gene
expression
or
optical
fiber
implantation.
A
significant
advancement
application
photoswitches
is
their
integration
with
flow
control
technology,
which
facilitates
targeting
deep
tissues
within
mouse
cerebral
cortex,
addressing
long‐standing
challenges
related
to
tissue
penetration
depth
photopharmacology.
With
exceptional
spatial
and
temporal
resolution,
photopharmacology
particularly
well‐suited
medicine,
holding
substantial
further
development.
Consequently,
a
comprehensive
summary
review
design
strategies
In
Vivo
applications,
along
experimental
outcomes,
are
essential
guiding
future
advancements
This
provides
an
overview
fundamental
properties
molecules.
Additionally,
we
summarize
all
molecules
successfully
applied
photopharmacological
purposes
since
2006,
covering
species
such
as
Caenorhabditis
elegans
,
Xenopus
tadpoles,
zebrafish,
mice,
rats,
rabbits,
canines.
Finally,
discuss
associated
implementation
propose
solutions.
Chemistry - A European Journal,
Год журнала:
2022,
Номер
28(63)
Опубликована: Июль 28, 2022
Photoswitchable
ligands
as
biological
tools
provide
an
opportunity
to
explore
the
kinetics
and
dynamics
of
clinically
relevant
μ-opioid
receptor.
These
can
potentially
activate
or
deactivate
receptor
when
desired
by
using
light.
Spatial
temporal
control
activity
allows
for
application
in
a
diverse
range
investigations.
have
been
developed
this
work,
modelled
on
known
agonist
fentanyl,
with
aim
expanding
current
"toolbox"
fentanyl
photoswitchable
ligands.
In
doing
so,
that
change
geometry
(isomerize)
upon
exposure
light,
varying
photophysical
biochemical
properties.
This
variation
properties
could
be
valuable
further
studying
functional
significance
Pharmacological Reviews,
Год журнала:
2023,
Номер
75(6), С. 1119 - 1139
Опубликована: Окт. 17, 2023
Despite
the
fact
that
roughly
40%
of
all
US
Food
and
Drug
Administration
(FDA)-approved
pharmacological
therapeutics
target
G
protein–coupled
receptors
(GPCRs),
there
remains
a
gap
in
our
understanding
physiologic
functional
role
these
at
systems
level.
Although
heterologous
expression
vitro
assays
have
revealed
tremendous
amount
about
GPCR
signaling
cascades,
how
cascades
interact
across
cell
types,
tissues,
organ
obscure.
Classic
behavioral
pharmacology
experiments
lack
both
temporal
spatial
resolution
to
resolve
long-standing
issues.
Over
past
half
century,
has
been
concerted
effort
toward
development
optical
tools
for
signaling.
From
initial
ligand
uncaging
approaches
more
recent
optogenetic
techniques,
strategies
allowed
researchers
probe
longstanding
questions
vivo
vitro.
These
employed
biologic
interrogation
everything
from
specific
intramolecular
events
level
spatiotemporally
manner.
In
this
review,
we
present
historical
perspective
on
motivation
behind
variety
toolkits
generated
Here
highlight
used
uncover
distinct
populations
GPCRs
their
Significance
Statement
(GPCRs)
remain
one
most
targeted
classes
proteins
pharmaceutical
intervention,
yet
still
limited
unique
effect
physiology
behavior
discuss
vast
array
techniques
devised
vivo.
iScience,
Год журнала:
2022,
Номер
25(9), С. 104882 - 104882
Опубликована: Авг. 5, 2022
In
this
study,
we
synthesized
and
evaluated
new
photoswitchable
ligands
for
the
beta-adrenergic
receptors
β1-AR
β2-AR,
applying
an
azologization
strategy
to
first-generation
beta-blocker
propranolol.
The
resulting
compounds
(Opto-prop-1,
-2,
-3)
have
good
photochemical
properties
with
high
levels
of
light-induced
trans-cis
isomerization
(>94%)
thermal
stability
(t1/2
>
10
days)
cis-isomer
in
aqueous
buffer.
Upon
illumination
360-nm
light
PSS
cis
,
large
differences
binding
affinities
were
observed
at
as
well
β2-AR.
Notably,
Opto-prop-2
(VUF17062)
showed
one
largest
optical
shifts
β2-AR
(587-fold,
cis-active),
recorded
so
far
photoswitches
G
protein-coupled
receptors.
We
finally
show
broad
utility
a
light-dependent
competitive
antagonist
shown
conformational
sensor,
by
recruitment
downstream
effector
proteins
functional
modulation
isolated
adult
rat
cardiomyocytes.
Biochemical Society Transactions,
Год журнала:
2023,
Номер
51(1), С. 13 - 20
Опубликована: Янв. 23, 2023
G
protein-coupled
receptor
(GPCR)
family
members
can
sense
an
extraordinary
variety
of
biomolecules
to
activate
intracellular
signalling
cascades
that
modulate
key
aspects
cell
physiology.
Apart
from
their
crucial
role
in
maintaining
homeostasis,
these
critical
sensory
and
modulatory
properties
have
made
GPCRs
the
most
successful
drug
target
class
date.
However,
establishing
direct
links
between
activation
specific
partners
individual
physiological
outcomes
is
still
ongoing
challenge.
By
studying
this
complexity
at
increasing
resolution
through
development
novel
biosensors
high-throughput
techniques,
a
growing
number
studies
are
revealing
how
function
be
diversified
spatial,
temporal
or
cell-specific
manner.
This
mini-review
will
introduce
recent
examples
context-dependent
discuss
it
impact
our
understanding
health
disease,
contribute
search
more
selective,
efficacious
safer
GPCR
candidates.
Angewandte Chemie International Edition,
Год журнала:
2024,
Номер
63(47)
Опубликована: Авг. 13, 2024
Abstract
The
field
of
G
protein‐coupled
receptor
(GPCR)
research
has
greatly
benefited
from
the
spatiotemporal
resolution
provided
by
light
controllable,
i.e
.,
photoswitchable
ligands.
Most
developed
tools
have
targeted
Rhodopsin‐like
family
(Class
A),
largest
GPCRs.
However,
to
date,
all
such
Class
A
ligands
were
designed
act
at
orthosteric
binding
site
these
receptors.
Herein,
we
report
development
first
allosteric
modulators
GPCRs,
target
M
1
muscarinic
acetylcholine
receptor.
presented
benzyl
quinolone
carboxylic
acid
(BQCA)
derivatives,
Photo‐BQC
is
and
tr
ns
,
exhibit
complementary
photopharmacological
behavior
allow
reversible
control
using
as
an
external
stimulus.
This
makes
them
valuable
further
investigate
signaling
a
proof
concept
for
Journal of Medicinal Chemistry,
Год журнала:
2023,
Номер
66(21), С. 14853 - 14865
Опубликована: Окт. 19, 2023
Oxytocin
(OT)
and
vasopressin
(VP)
are
related
neuropeptides
that
regulate
many
biological
processes.
In
humans,
OT
VP
act
via
four
G
protein-coupled
receptors,
OTR,
V1aR,
V1bR,
V2R
(VPRs),
which
associated
with
several
disorders.
To
investigate
the
therapeutic
potential
of
these
particularly
in
receptor-dense
areas
brain,
molecular
probes
a
high
temporal
spatial
resolution
required.
Such
spatiotemporal
can
be
achieved
by
incorporating
photochromic
moieties
into
VP.
Here,
we
report
design,
synthesis,
(photo)pharmacological
characterization
12
OT-
VP-derived
photoprobes
using
different
modification
strategies.
Despite
OT's
VP's
sensitivity
toward
structural
changes,
identified
two
good
potency
photoswitch
window
for
investigating
OTR
V1bR.
These
should
value
producing
cutting-edge
photocontrollable
peptide
study
dynamic
kinetic
receptor
activation
processes
specific
regions
brain.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Март 25, 2024
1.
Abstract
Photopharmacology
offers
the
promise
of
optical
modulation
cellular
signaling
in
a
spatially
and
temporally
controlled
fashion
with
light-sensitive
molecules.
This
study
presents
first
small-molecule
photoswitchable
agonist
for
an
atypical
G
protein-coupled
receptor
(GPCR),
chemokine
3
(ACKR3).
Inspired
by
known
benzylpiperidine-based
ACKR3
scaffold,
12
azobenzene-containing
analogs
were
synthesized
characterized
their
interaction
ACKR3.
After
analysis
Structure-Photochemistry
Structure-Affinity
Relationships
(SAR),
compound
3e
was
selected
as
best
series.
Compound
can
be
effectively
switched
from
its
thermodynamically
stable
trans
state
to
less
active
cis
-isomer
PhotoStationary
State
96
%.
The
cis-
only
slowly
switches
back
(t
1/2,37
°C
=
15
days),
trans-
binds
activates
at
10-fold
lower
concentrations
compared
-isomer.
demonstrates
selectivity
within
panel
receptors.
Using
recently
published
cryo-EM
structures
computational
studies,
binding
mode
is
proposed
perfectly
line
observed
SAR
loss
upon
photoswitching.
(VUF25471)
ligand
GPCR
will
useful
tool
investigate
role
biological
settings.
Angewandte Chemie,
Год журнала:
2024,
Номер
136(47)
Опубликована: Авг. 13, 2024
Abstract
Das
Forschungsgebiet
der
G‐Protein‐gekoppelten
Rezeptoren
(GPCRs)
hat
stark
vom
Gewinn
an
räumlich‐zeitlicher
Auflösung
profitiert,
mit
Entwicklung
licht‐kontrollierbarer
und
‐schaltbarer
Verbindungen
einhergeht.
Die
meisten
synthetisierten
molekularen
Werkzeuge
adressieren
die
Klasse
A
GPCRs
(Rhodopsin‐ähnlich),
größte
Subfamilie
dieser
Rezeptorklasse.
All
diese
wurden
entworfen,
um
orthosterische
Bindungsstelle
zu
adressieren.
In
Arbeit
berichten
wir
über
ersten
photoschaltbaren
allosterischen
Modulatoren
GPCRs,
entwickelt
wurden,
den
muscarinischen
Acetylcholinrezeptor
Subtyp
1
(M
)
aktivieren.
dargestellten
Derivate
Benzylchinoloncarbonsäure
(BQCA),
nämlich
Photo‐BQC
is
and
tr
ns
,
zeigen
komplementäres
photopharmakologisches
Verhalten
erlauben
reversible
Kontrolle
M
R
mittels
Licht
als
externem
Stimulus.
Dieses
lässt
Substanzen
wertvoll
erscheinen,
etwa
das
R‐Signalling
untersuchen
zudem
dient
Machbarkeitsstudie
für
Darstellung
anderer
photoschaltbarer
A‐Rezeptoren
