10 research outputs found
Novel 1<i>H</i>‑Pyrrolo[3,2‑<i>c</i>]quinoline Based 5‑HT<sub>6</sub> Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer’s Disease
Modulators of the serotonin 5-HT<sub>6</sub> receptor (5-HT<sub>6</sub>R) offer a promising strategy for
the treatment of the cognitive
deficits that are associated with dementia and Alzheimer’s
disease. Herein, we report the design, synthesis, and characterization
of a novel class of 5-HT<sub>6</sub>R antagonists that is based on
the 1<i>H</i>-pyrrolo[3,2-<i>c</i>]quinoline core.
The most active compounds exhibited comparable binding affinity to
the reference compound, SB-742457, and markedly improved selectivity.
Lead optimization led to the identification of (<i>S</i>)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1<i>H</i>-pyrrolo[3,2-<i>c</i>]quinoline (<b>14</b>) (<i>K</i><sub>i</sub> = 3 nM and <i>K</i><sub>b</sub> = 0.41 nM). Pharmacological characterization of the 5-HT<sub>6</sub>R’s constitutive activity at Gs signaling revealed
that <b>14</b> behaved as a neutral antagonist, while SB-742457
was classified as an inverse agonist. Both compounds <b>14</b> and SB-742457 reversed phencyclidine-induced memory deficits and
displayed distinct procognitive properties in cognitively unimpaired
animals (3 mg/kg) in NOR tasks. Compounds <b>14</b> and SB-742457
were also active in the Vogel test, yet the anxiolytic effect of <b>14</b> was 2-fold higher (MED = 3 mg/kg). Moreover, <b>14</b> produced, in a 3-fold higher dose (MED = 10 mg/kg), antidepressant-like
effects that were similar to those produced by SB-742457 (MED = 3
mg/kg). Together, these data suggest that the 4-(pyrrolidine-3-yl-amino)-1<i>H</i>-pyrrolo[3,2-<i>c</i>]quinoline scaffold is an
attractive molecular framework for the development of procognitive
agents. The results are promising enough to warrant further detailed
mechanistic studies on the therapeutic potential of 5-HT<sub>6</sub>R antagonists and inverse agonists for the treatment of cognitive
decline and depression/anxiety symptoms that are comorbidities of
Alzheimer’s disease
Superiority of the Triple-Acting 5‑HT<sub>6</sub>R/5-HT<sub>3</sub>R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT<sub>6</sub>R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
The multifactorial
origin and neurochemistry of Alzheimer’s
disease (AD) call for the development of multitarget treatment strategies.
We report a first-in-class triple acting compound that targets serotonin
type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B)
as an approach for treating AD. The key structural features required
for MAO-B inhibition and 5-HT6R antagonism and interaction
with 5-HT3R were determined using molecular dynamic simulations
and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object
recognition test. Furthermore, it displayed superior pro-cognitive
properties compared to intepirdine (a 5-HT6R antagonist)
in the AD model, which involved intracerebroventricular injection
of an oligomeric solution of amyloid-β peptide (oAβ) in
the T-maze test in rats. PZ-1922, but not intepirdine,
restored levels of biomarkers characteristic of the debilitating effects
of oAβ. These data support the potential of a multitarget approach
involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD
Superiority of the Triple-Acting 5‑HT<sub>6</sub>R/5-HT<sub>3</sub>R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT<sub>6</sub>R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
The multifactorial
origin and neurochemistry of Alzheimer’s
disease (AD) call for the development of multitarget treatment strategies.
We report a first-in-class triple acting compound that targets serotonin
type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B)
as an approach for treating AD. The key structural features required
for MAO-B inhibition and 5-HT6R antagonism and interaction
with 5-HT3R were determined using molecular dynamic simulations
and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object
recognition test. Furthermore, it displayed superior pro-cognitive
properties compared to intepirdine (a 5-HT6R antagonist)
in the AD model, which involved intracerebroventricular injection
of an oligomeric solution of amyloid-β peptide (oAβ) in
the T-maze test in rats. PZ-1922, but not intepirdine,
restored levels of biomarkers characteristic of the debilitating effects
of oAβ. These data support the potential of a multitarget approach
involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD
Superiority of the Triple-Acting 5‑HT<sub>6</sub>R/5-HT<sub>3</sub>R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT<sub>6</sub>R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
The multifactorial
origin and neurochemistry of Alzheimer’s
disease (AD) call for the development of multitarget treatment strategies.
We report a first-in-class triple acting compound that targets serotonin
type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B)
as an approach for treating AD. The key structural features required
for MAO-B inhibition and 5-HT6R antagonism and interaction
with 5-HT3R were determined using molecular dynamic simulations
and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object
recognition test. Furthermore, it displayed superior pro-cognitive
properties compared to intepirdine (a 5-HT6R antagonist)
in the AD model, which involved intracerebroventricular injection
of an oligomeric solution of amyloid-β peptide (oAβ) in
the T-maze test in rats. PZ-1922, but not intepirdine,
restored levels of biomarkers characteristic of the debilitating effects
of oAβ. These data support the potential of a multitarget approach
involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD
Superiority of the Triple-Acting 5‑HT<sub>6</sub>R/5-HT<sub>3</sub>R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT<sub>6</sub>R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
The multifactorial
origin and neurochemistry of Alzheimer’s
disease (AD) call for the development of multitarget treatment strategies.
We report a first-in-class triple acting compound that targets serotonin
type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B)
as an approach for treating AD. The key structural features required
for MAO-B inhibition and 5-HT6R antagonism and interaction
with 5-HT3R were determined using molecular dynamic simulations
and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object
recognition test. Furthermore, it displayed superior pro-cognitive
properties compared to intepirdine (a 5-HT6R antagonist)
in the AD model, which involved intracerebroventricular injection
of an oligomeric solution of amyloid-β peptide (oAβ) in
the T-maze test in rats. PZ-1922, but not intepirdine,
restored levels of biomarkers characteristic of the debilitating effects
of oAβ. These data support the potential of a multitarget approach
involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD
Superiority of the Triple-Acting 5‑HT<sub>6</sub>R/5-HT<sub>3</sub>R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT<sub>6</sub>R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
The multifactorial
origin and neurochemistry of Alzheimer’s
disease (AD) call for the development of multitarget treatment strategies.
We report a first-in-class triple acting compound that targets serotonin
type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B)
as an approach for treating AD. The key structural features required
for MAO-B inhibition and 5-HT6R antagonism and interaction
with 5-HT3R were determined using molecular dynamic simulations
and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object
recognition test. Furthermore, it displayed superior pro-cognitive
properties compared to intepirdine (a 5-HT6R antagonist)
in the AD model, which involved intracerebroventricular injection
of an oligomeric solution of amyloid-β peptide (oAβ) in
the T-maze test in rats. PZ-1922, but not intepirdine,
restored levels of biomarkers characteristic of the debilitating effects
of oAβ. These data support the potential of a multitarget approach
involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD
Superiority of the Triple-Acting 5‑HT<sub>6</sub>R/5-HT<sub>3</sub>R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT<sub>6</sub>R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
The multifactorial
origin and neurochemistry of Alzheimer’s
disease (AD) call for the development of multitarget treatment strategies.
We report a first-in-class triple acting compound that targets serotonin
type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B)
as an approach for treating AD. The key structural features required
for MAO-B inhibition and 5-HT6R antagonism and interaction
with 5-HT3R were determined using molecular dynamic simulations
and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object
recognition test. Furthermore, it displayed superior pro-cognitive
properties compared to intepirdine (a 5-HT6R antagonist)
in the AD model, which involved intracerebroventricular injection
of an oligomeric solution of amyloid-β peptide (oAβ) in
the T-maze test in rats. PZ-1922, but not intepirdine,
restored levels of biomarkers characteristic of the debilitating effects
of oAβ. These data support the potential of a multitarget approach
involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD
Superiority of the Triple-Acting 5‑HT<sub>6</sub>R/5-HT<sub>3</sub>R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT<sub>6</sub>R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
The multifactorial
origin and neurochemistry of Alzheimer’s
disease (AD) call for the development of multitarget treatment strategies.
We report a first-in-class triple acting compound that targets serotonin
type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B)
as an approach for treating AD. The key structural features required
for MAO-B inhibition and 5-HT6R antagonism and interaction
with 5-HT3R were determined using molecular dynamic simulations
and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object
recognition test. Furthermore, it displayed superior pro-cognitive
properties compared to intepirdine (a 5-HT6R antagonist)
in the AD model, which involved intracerebroventricular injection
of an oligomeric solution of amyloid-β peptide (oAβ) in
the T-maze test in rats. PZ-1922, but not intepirdine,
restored levels of biomarkers characteristic of the debilitating effects
of oAβ. These data support the potential of a multitarget approach
involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD
Stem Cell Factor in Combination With Filgrastim After Chemotherapy Improves Peripheral Blood Progenitor Cell Yield and Reduces Apheresis Requirements in Multiple Myeloma Patients: A Randomized, Controlled Trial
The detection of polarized X-ray emission from the magnetar 1E 2259+586
International audienceWe report on IXPE, NICER, and XMM-Newton observations of the magnetar 1E 2259+586. We find that the source is significantly polarized at about or above 20 per cent for all phases except for the secondary peak where it is more weakly polarized. The polarization degree is strongest during the primary minimum which is also the phase where an absorption feature has been identified previously. The polarization angle of the photons are consistent with a rotating vector model with a mode switch between the primary minimum and the rest of the rotation of the neutron star. We propose a scenario in which the emission at the source is weakly polarized (as in a condensed surface) and, as the radiation passes through a plasma arch, resonant cyclotron scattering off of protons produces the observed polarized radiation. This confirms the magnetar nature of the source with a surface field greater than about 1015 G