Novel 1<i>H</i>‑Pyrrolo[3,2‑<i>c</i>]quinoline Based 5‑HT₆ Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer’s Disease

Modulators of the serotonin 5-HT₆ receptor (5-HT₆R) 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-HT₆R 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>_i = 3 nM and <i>K</i>_b = 0.41 nM). Pharmacological characterization of the 5-HT₆R’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-HT₆R 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‑HT₆R/5-HT₃R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT₆R 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‑HT₆R/5-HT₃R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT₆R 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‑HT₆R/5-HT₃R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT₆R 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‑HT₆R/5-HT₃R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT₆R 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‑HT₆R/5-HT₃R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT₆R 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‑HT₆R/5-HT₃R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT₆R 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‑HT₆R/5-HT₃R Antagonist and MAO‑B Reversible Inhibitor <b>PZ-1922</b> over 5‑HT₆R 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

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