Genes & Diseases,
Год журнала:
2024,
Номер
12(4), С. 101480 - 101480
Опубликована: Дек. 4, 2024
Regulator
of
G
protein
signaling
12
(RGS12)
belongs
to
the
superfamily
RGS
proteins
defined
by
a
conserved
domain
that
canonically
binds
and
deactivates
heterotrimeric
G-proteins.
As
largest
family
member,
RGS12
is
widely
expressed
in
many
cells
tissues.
In
past
few
decades,
it
has
been
found
affects
activity
various
human
body,
participates
physiological
pathological
processes,
plays
an
important
role
pathogenesis
diseases.
Here,
we
set
out
comprehensively
review
diseases
its
mechanisms,
highlighting
possibility
as
therapeutic
target
for
treatment
ACS Central Science,
Год журнала:
2024,
Номер
10(8), С. 1490 - 1503
Опубликована: Июль 17, 2024
The
mu
opioid
receptor
(μOR)
is
a
target
for
clinically
used
analgesics.
However,
adverse
effects,
such
as
respiratory
depression
and
physical
dependence,
necessitate
the
development
of
alternative
treatments.
Recently
we
reported
novel
strategy
to
design
functionally
selective
opioids
by
targeting
sodium
binding
allosteric
site
in
μOR
with
supraspinally
active
analgesic
named
C6guano.
Presently,
improve
systemic
activity
this
ligand,
structure-based
design,
identifying
new
ligand
RO76
where
flexible
alkyl
linker
polar
guanidine
guano
group
swapped
benzyl
alcohol,
targeted
indirectly
through
waters.
A
cryoEM
structure
bound
μOR-Gi
complex
confirmed
that
interacts
residues
water
molecule,
unlike
C6guano
which
engages
directly.
Signaling
assays
coupled
APEX
based
proximity
labeling
show
pocket
modulates
efficacy
trafficking.
In
mice,
was
systemically
tail
withdrawal
showed
reduced
liabilities
compared
those
morphine.
summary,
molecules
may
be
an
avenue
modulate
signaling
properties
opioids,
potentially
extended
other
G-protein
receptors
conserved.
Molecular Pharmacology,
Год журнала:
2024,
Номер
106(5), С. 240 - 252
Опубликована: Авг. 26, 2024
Ketamine
is
a
glutamate
receptor
antagonist
that
was
developed
over
50
years
ago
as
an
anesthetic
agent.
At
subanesthetic
doses,
ketamine
and
some
metabolites
are
analgesics
fast-acting
antidepressants,
presumably
through
targets
other
than
receptors.
We
tested
its
for
activity
allosteric
modulators
of
opioid
receptors
expressed
recombinant
in
heterologous
systems
with
native
rodent
brain;
signaling
examined
by
measuring
GTP
binding,
Trends in Pharmacological Sciences,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
Activation
of
the
μ
opioid
receptor
(MOR)
can
give
analgesia,
but
also
has
dangerous
side
effects.
Drugs
that
target
MOR
through
an
allosteric
site,
meaning
they
bind
outside
usual
pocket,
present
a
novel
mode
activation
with
different
pharmacology
relative
to
orthosteric
drugs.
Recent
structural
studies
valuable
new
information
on
how
modulators
interact
MOR.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Март 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.
Chemical and Pharmaceutical Bulletin,
Год журнала:
2025,
Номер
73(3), С. 246 - 256
Опубликована: Март 28, 2025
The
δ-opioid
receptor
(DOR)
is
a
promising
target
for
developing
novel
analgesics
due
to
its
lower
risk
of
causing
side
effects
compared
the
μ-opioid
(MOR),
which
commonly
associated
with
dependence,
respiratory
depression,
and
other
adverse
effects.
KNT-127,
DOR-selective
agonist
morphinan
skeleton,
offers
analgesic
antidepressant
benefits
without
inducing
convulsions
at
therapeutic
doses,
unlike
conventional
DOR
SNC80.
While
previous
studies
have
suggested
that
KNT-127
exhibits
reduced
β-arrestin
recruitment,
signaling
pathway
implicated
in
opioid
effects,
ligand
structural
basis
this
biased
remains
unclear.
In
study,
we
explored
structure-signal
relationships
focusing
on
quinoline
moiety,
known
serve
as
an
address
domain
responsible
selectivity.
Modifying
moiety
by
removing
aromatic
rings
selectivity
potency
relation
G-protein
activation
while
diminishing
both
efficacy
recruitment.
These
results
suggest
skeleton
critical
differentially
modulates
Together,
our
study
expands
message-address
concept,
previously
limited
selectivity,
providing
insights
into
G-protein-biased
agonism
agonists,
thereby
guiding
design
safer
DOR-targeting
therapeutics.
CNS Neuroscience & Therapeutics,
Год журнала:
2024,
Номер
30(9)
Опубликована: Сен. 1, 2024
Abstract
Aims
Opioid
use
disorder
(OUD)
remains
a
serious
public
health
problem.
maintenance
treatment
is
effective
but
under‐utilized,
hard
to
access
under
existing
federal
regulations,
and,
once
patients
achieve
OUD
stability,
challenging
discontinue.
Fewer
than
2%
of
persons
with
stop
using
opioids
completely.
There
have
been
calls
from
advocacy
groups,
governmental
agencies,
and
officials
for
new
treatments
OUD.
Dezocine,
non‐scheduled
opioid
previously
used
in
the
United
States
currently
widely
prescribed
China
pain
management,
could
be
candidate
novel
medication
U.S.
Nonetheless,
date,
there
no
reviews
clinical
preclinical
literature
detailing
dezocine's
abuse
potential,
key
consideration
assessing
its
utility.
Discussion
are
English
language
reports
human
abuse,
dependence,
or
overdose
dezocine,
despite
years
extensive
use.
few
case
dezocine
Chinese
literature,
deaths.
Dezocine
perceived
as
an
“liked”
by
opioid‐experienced
non‐human
primates,
properties
that
not
dose‐dependent
mitigated
ceiling
effects—higher
doses
do
result
more
“liking.”
little
withdrawal,
spontaneous
precipitated,
humans,
monkeys,
rats,
mice
treated
chronically
alone.
However,
at
some
doses,
can
precipitate
withdrawal
humans
monkeys
dependent
on
other
opioids.
In
rodents,
reduces
severity
morphine
rewarding
Conclusions
Although
reinforcing
prior
concurrent
within
restricted
dose
range,
only
anecdotal
long
history
humans.
Given
evidence
limited
it
useful
both
in‐depth
studies
would
required
re‐considered
