Tryptophan
plays
a
critical
role
in
diverse
natural
products,
biological
processes,
and
pharmaceutical
molecules.
Facile
access
to
this
amino
acid
its
analogues
from
readily
available
building
blocks,
however,
remains
long-standing
challenge.
Here,
we
report
regioselective
synthesis
of
tryptophan
unnatural
variants
bearing
C4-C7
substituents
via
Rh-catalyzed
annulation
between
structurally
tert-butyloxycarbonyl
(Boc)
protected
anilines
serine
derived
alkynyl
chloride.
This
transformation
features
C-H
activation
directed
by
weakly
coordinating
Boc
group,
the
umpolung
reactivity
chloride,
acetic
acid-mediated
reverse
rhodation
afford
C2
unsubstituted
indole
products
redox-neutral
fashion.
The
wide
utility
chemistry
is
demonstrated
for
halogenated,
borylated,
poly-oxygenated
tryptophans,
drug
analogues,
dipeptides
with
crosslinks
on
tryptophan,
heterocycle-containing
derivatives.
reaction
will
facilitate
preparation
compounds,
notably
myriad
bioactive
Trp-containing
products.
European Archives of Psychiatry and Clinical Neuroscience,
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 27, 2024
The
growing
interest
in
the
rapid
and
sustained
antidepressant
effects
of
dissociative
anesthetic
ketamine
classic
psychedelics,
such
as
psilocybin,
is
remarkable.
However,
both
psychedelics
are
known
to
induce
acute
mystical
experiences;
can
cause
symptoms
out-of-body
experience,
while
typically
bring
about
hallucinogenic
experiences,
like
a
profound
sense
unity
with
universe
or
nature.
role
these
experiences
enhancing
outcomes
for
patients
depression
currently
an
area
ongoing
investigation
debate.
Clinical
studies
have
shown
that
following
administration
(S)-ketamine
(esketamine)
not
directly
linked
their
properties.
In
contrast,
potential
(R)-ketamine
(arketamine),
thought
lack
side
effects,
has
yet
be
conclusively
proven
large-scale
clinical
trials.
Moreover,
although
activation
serotonin
5-HT
ACS Medicinal Chemistry Letters,
Год журнала:
2025,
Номер
16(2), С. 192 - 193
Опубликована: Янв. 8, 2025
Provided
herein
are
novel
pyridine
derivatives
as
5-HT2A
agonists,
pharmaceutical
compositions,
use
of
such
compounds
in
treating
psychiatric
disorders,
and
processes
for
preparing
compounds.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Май 29, 2024
Abstract
G
protein-coupled
receptors
(GPCRs)
are
sophisticated
signaling
machines
able
to
simultaneously
elicit
multiple
intracellular
pathways
upon
activation.
Complete
(in)activation
of
all
can
be
counterproductive
for
specific
therapeutic
applications.
This
is
the
case
serotonin
2
A
receptor
(5-HT
2A
R),
a
prominent
target
treatment
schizophrenia.
In
this
study,
we
elucidate
complex
5-HT
R
coupling
signature
in
response
different
probes,
and
its
physiological
consequences
by
combining
computational
modeling,
vitro
vivo
experiments
with
human
postmortem
brain
studies.
We
show
how
chemical
modification
endogenous
agonist
dramatically
impacts
protein
profile
associated
behavioral
responses.
Importantly,
among
these
responses,
demonstrate
that
memory
deficits
regulated
αq
activation,
whereas
psychosis-related
behavior
modulated
through
αi1
stimulation.
These
findings
emphasize
complexity
GPCR
pharmacology
physiology
open
path
designing
improved
therapeutics
stchizophrenia.
Progress in Neuro-Psychopharmacology and Biological Psychiatry,
Год журнала:
2025,
Номер
unknown, С. 111243 - 111243
Опубликована: Янв. 1, 2025
Chronic
stress
exerts
profound
effects
on
mental
health,
contributing
to
disorders
such
as
depression,
anxiety,
and
cognitive
impairment.
This
study
examines
the
potential
of
psilocybin
alleviate
behavioral
despair
deficits
in
a
rodent
model
chronic
stress,
focusing
interplay
between
Hypothalamic-Pituitary-Adrenal
(HPA)
axis
Endocannabinoid
System
(ECS).
Twenty-two
male
Wistar
rats
were
divided
into
control
groups.
Animals
within
group
exposed
predator
odor
social
instability
induce
either
sham
treated,
or
given
psilocybin.
Behavioral
assessments
conducted
using
Open
Field
Test,
Sucrose
Preference
Novel
Object
Recognition,
Elevated
Plus
Maze,
Forced
Swimming
Test
evaluate
locomotion,
anhedonia,
memory,
despair,
respectively.
Blood
brain
samples
analyzed
for
biochemical
markers.
Results
indicated
that
significantly
reduced
stress-induced
impairments,
likely
through
ECS-mediated
downregulation
HPA
axis.
These
findings
suggest
early
intervention
with
has
sustained
beneficial
stress-related
disturbances,
underscoring
its
novel
therapeutic
approach
health
disorders.
5HT
2A
R
is
a
G‐protein‐coupled
receptor
that
drives
many
neuronal
functions
and
target
for
psychedelic
drugs.
Understanding
ligand
interactions
conformational
transitions
essential
developing
effective
pharmaceuticals,
but
mechanistic
details
of
activation
remain
poorly
understood.
We
utilized
all‐atom
molecular
dynamics
simulations
free‐energy
calculations
to
investigate
R's
upon
binding
serotonin
psilocin.
show
the
active
state
collapses
closed
in
absence
Gqα,
underscoring
importance
G‐protein
coupling.
discover
an
intermediate
“partially‐open”
conformation.
Both
ligands
have
higher
affinities
orthosteric
than
extended
pocket.
These
findings
enhance
our
understanding
may
aid
novel
therapeutics.
Impact
statement
This
study
sheds
light
on
activation,
revealing
conformations
dynamics.
insights
could
drug
development
neurological
psychiatric
disorders,
benefiting
researchers
clinicians
pharmacology
neuroscience.
ACS Medicinal Chemistry Letters,
Год журнала:
2024,
Номер
16(1), С. 18 - 19
Опубликована: Дек. 10, 2024
Provided
herein
are
novel
3-pyrrolidineindole
derivatives
as
serotonergic
psychedelic
agents,
pharmaceutical
compositions,
use
of
such
compounds
in
treating
psychosis
and
mental
illnesses
depression
post-traumatic
stress
disorder,
processes
for
preparing
compounds.
British Journal of Pharmacology,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 23, 2025
Psychedelic
drugs
such
as
LSD
and
psilocin
were
once
relegated
to
the
fringes
of
medical
research
because
their
association
with
counterculture
movements
a
perceived
concern
about
harm
through
recreational
use,
consequent
legal
prohibition
in
early
1970s.
However,
these
are
now
experiencing
renaissance
field
psychiatry
based
on
increasing
evidence
that
they
can
produce
long‐lasting
improvements
health
across
wide
variety
mental
illnesses,
including
major
depression,
addictions
anxiety
disorders.
These
interact
many
different
5‐HT
receptor
subtypes
but
powerful
psychedelic
experience,
which
(depending
set
setting)
includes
profound
alterations
perception,
mood
cognition,
accompanied
by
vivid
hallucinations,
is
widely
considered
mediated
an
agonist
action
at
2A
receptors.
link
between
agonism
therapeutic
effects
currently
uncertain.
Indeed,
recent
has
revealed
new
class
agonists
appear
retain
potential
psychedelics
without
inducing
disorienting
hallucinatory
experiences.
Biased
signalling,
partial
non‐selectivity
amongst
possible
explanations
for
differential
properties
drugs,
whereas
increased
neuroplasticity
offers
likely
account
common
effects.
This
article
explores
neuropsychopharmacological
hallucinogenic
non‐hallucinogenic
context
promise
novel
drug
treatments
psychiatry.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(9), С. 7224 - 7244
Опубликована: Апрель 22, 2024
Classical
psychedelics
such
as
psilocybin,
lysergic
acid
diethylamide
(LSD),
and
N,N-dimethyltryptamine
(DMT)
are
showing
promising
results
in
clinical
trials
for
a
range
of
psychiatric
indications,
including
depression,
anxiety,
substance
abuse
disorder.
These
compounds
characterized
by
broad
pharmacological
activity
profiles,
while
the
acute
mind-altering
effects
can
be
ascribed
to
their
shared
agonist
at
serotonin
2A
receptor
(5-HT2AR),
apparent
persistent
therapeutic
yet
decidedly
linked
this
receptor.
We
report
herein
discovery
2,5-dimethoxyphenylpiperidines
novel
class
selective
5-HT2AR
agonists
detail
structure–activity
investigations
leading
identification
LPH-5
[analogue
(S)-11]
with
desirable
drug-like
properties.
