Prophylactic efficacy of serotonin 4 receptor agonists against stress

An agonist, serotonin-based technology for the treatment or prevention of stress-induced affective disorders, such as post-traumatic stress disorder, to address issues such as unmet

Pending Publication Date: 2022-01-11
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] There is an unmet need for effective preventive therapies to prevent the onset of stress-induced affective disorders

Method used

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  • Prophylactic efficacy of serotonin 4 receptor agonists against stress
  • Prophylactic efficacy of serotonin 4 receptor agonists against stress
  • Prophylactic efficacy of serotonin 4 receptor agonists against stress

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0209] Example 1: Preventive efficacy of 5-HT4R agonists against stress

[0210] Enhanced stress resilience protects high-risk populations from stress-induced psychosis. We previously reported that (R,S)-ketamine acts as a prophylactic against stress when administered 1 week before stress. Although we have shown that the selective serotonin (5-HT) (serotonin) reuptake inhibitor (SSRI) fluoxetine (Flx) is not effective as a preventive agent, we hypothesized that other serotonergic compounds such as serotonin 4 receptor (5-HT 4 R) Agonists may act as preventive agents. We tested three 5-HT with different affinity 4 Whether R agonists can prevent stress in two mouse strains by utilizing chronic corticosterone (CORT) administration or contextual fear conditioning (CFC). Mice were administered different doses of saline, (R,S)-ketamine, Flx, RS-67,333, prucalopride, or PF-04995274, and then received chronic CORT or CFC 1 week later. In C57BL / 6N mice, chronic Flx administration ...

Embodiment 2

[0381] Example 2 The rapid anxiolytic effect of RS67333 (a serotonin type 4 receptor agonist) and diazepam (a benzodiazepine) is mediated by projections from the prefrontal cortex to the dorsal raphe nucleus

[0382] summary

[0383] background : Activate serotonin (5-HT) 4 receptor (5-HT 4 R) has been shown to have anxiolytic effects in various animal models. Characterizing the circuits responsible for these effects should provide insights into new approaches to treating anxiety.

[0384] method : We evaluated acute 5-HT in glutamatergic axon terminals originating from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN) 4 Does R activation induce rapid anxiolytic effects. Acute systemic administration (1.5 mg / kg, intraperitoneal, i.p.) or intramPFC infusion of 5-HT was examined in mice 4 Anxiolytic effects of the R agonist RS67333 (0.5 mg / side). To provide evidence that the anxiolytic effects of RS67333 recruit mPFC-DRN neural circuits, in vivo reco...

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PUM

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Abstract

Methods for prophylactically treating a stress-induced affective disorder or stress-induced psychopathology in a subject are provided. Also provided are methods for inducing and / or enhancing stress resilience in a subject. In certain embodiments, an effective amount of an agonist of the serotonin 4 receptor (5-HT4R), or a pharmaceutically acceptable salt or derivative thereof, is administered to a subject prior to a stressor.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Patent Application No. 62 / 831,517, filed April 9, 2019, U.S. Provisional Patent Application No. 62 / 857,075, filed June 4, 2019, and U.S. Provisional Patent Application No. 62 / 857,075, filed October 4, 2019. Priority to patent application Ser. No. 62 / 910,859, each of which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to serotonin 4 receptors (5-hydroxytryptamine (serotonin) receptor 4 or 5-HT 4 R) Agonist compositions and their use in methods of treating or preventing stress-induced affective disorders such as post-traumatic stress disorder (PTSD). In certain aspects, compositions of the invention may be administered prior to the stressor. [0004] Background of the invention [0005] Stress exposure is an important factor in the development of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/138
CPCA61K31/445A61K31/4525A61K31/453A61K45/06A61P25/22A61P25/24A61K2300/00A61K31/454
Inventor C·A·丹尼A·M·加德尔D·J·大卫I·门德斯-大卫C·费伊B·K·陈
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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