Genes & Diseases,
Journal Year:
2024,
Volume and Issue:
12(4), P. 101480 - 101480
Published: Dec. 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
Medicinal Research Reviews,
Journal Year:
2024,
Volume and Issue:
44(6), P. 2545 - 2599
Published: May 15, 2024
Abstract
Opioid
receptors
belonging
to
the
class
A
G‐protein
coupled
(GPCRs)
are
targets
of
choice
in
treatment
acute
and
chronic
pain.
However,
their
on‐target
side
effects
such
as
respiratory
depression,
tolerance
addiction
have
led
advent
‘opioid
crisis’.
In
search
for
safer
analgesics,
bivalent
more
recently,
bitopic
ligands
emerged
valuable
tool
compounds
probe
these
receptors.
The
activity
rely
greatly
on
allosteric
nature
GPCRs.
Bivalent
consist
two
pharmacophores,
each
binding
individual
orthosteric
site
(OBS)
monomers
within
a
dimer.
Bitopic
or
dualsteric
bridge
gap
between
OBS
spatially
distinct,
less
conserved
(ABS)
through
simultaneous
occupation
sites.
stabilize
distinct
conformations
which
ultimately
translates
into
unique
signalling
pharmacological
profiles.
Some
interesting
properties
shown
by
include
improved
affinity
and/or
efficacy,
subtype
functional
selectivity
reduced
effects.
This
review
aims
at
providing
an
overview
some
opioid
and,
pharmacology
hope
inspiring
design
discovery
next
generation
analgesics.
Pharmacological Research,
Journal Year:
2024,
Volume and Issue:
210, P. 107503 - 107503
Published: Nov. 7, 2024
2-Benzylbenzimidazole
derivatives
or
'nitazenes'
are
increasingly
present
on
the
recreational
drug
market.
Here,
we
report
synthesis
and
pharmacological
characterization
of
15
structurally
diverse
nitazenes
that
might
be
predicted
to
emerge
grow
in
popularity.
This
work
expands
existing
knowledge
about
2-benzylbenzimidazole
structure-activity
relationships
(SARs),
while
also
helping
stakeholders
(e.g.,
forensic
toxicologists,
clinicians,
policymakers)
their
risk
assessment
preparedness
for
potential
next
generation
nitazenes.
In
vitro
µ-opioid
receptor
(MOR)
affinity
was
determined
via
competition
radioligand
(
Current Opinion in Pharmacology,
Journal Year:
2024,
Volume and Issue:
76, P. 102465 - 102465
Published: June 1, 2024
Ligand
bias
offers
a
novel
means
to
improve
the
therapeutic
profile
of
drugs.
With
regard
G
protein-coupled
receptors
involved
in
analgesia,
it
could
be
advantageous
develop
such
drugs
if
analgesic
effect
is
mediated
by
different
cellular
signalling
pathway
than
adverse
effects
associated
with
drug.
Whilst
this
has
been
explored
over
number
years
for
μ
receptor,
remains
unclear
whether
approach
significant
benefit
treatment
pain.
Nevertheless,
development
biased
ligands
at
other
CNS
does
offer
some
promise
future.
Here
we
summarise
and
discuss
recent
evidence
support
this.
Research Square (Research Square),
Journal Year:
2024,
Volume and Issue:
unknown
Published: July 16, 2024
Abstract
The
persistence
of
chronic
pain
and
continuing
overdose
deaths
from
pain-relieving
opioids
targeting
µ
opioid
receptor
(µOR)
have
fueled
the
need
for
reliable
long-term
analgesics
which
use
different
targets
mechanisms.
δ
(δOR)
is
a
potential
alternative
target
non-addictive
to
alleviate
pain,
made
more
attractive
by
its
lack
respiratory
depression
associated
with
µOR
agonists.
However,
early
δOR
full
agonists
were
found
induce
seizures,
precluding
clinical
use.
Partial
may
offer
controlled
activation
compared
agonists,
but
development
such
ligands
has
been
hindered
uncertainty
over
molecular
mechanism
mediating
partial
agonism.
Using
structure-based
approach,
we
explored
engagement
sodium
binding
pocket
in
developed
bitopic
ligand,
C6-Quino,
predicted
be
selective
agonist.
Functional
studies
C6-Quino
revealed
that
it
displayed
agonist
activity
at
both
G-protein
arrestin
pathways.
Its
interaction
was
confirmed
analyzed
using
single
particle
cryo-EM.
Additionally,
demonstrated
favorable
chemical
physiological
properties
like
oral
activity,
analgesic
multiple
models.
Notably,
µOR-related
hyperlocomotion
depression,
δOR-related
convulsions,
not
observed
doses
C6-Quino.
This
fundamentally
new
approach
designing
provides
blueprint
as
safe
acts
generic
method
optimize
signaling
profiles
other
Class
A
GPCRs.
Genes & Diseases,
Journal Year:
2024,
Volume and Issue:
12(4), P. 101480 - 101480
Published: Dec. 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
