Serotonin type 6 receptor inverse agonists and neutral antagonists inhibit defecation: relevance to intestinal motility disorders

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F25%3A73632452" target="_blank" >RIV/61989592:15310/25:73632452 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0014299925008532" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0014299925008532</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejphar.2025.178099" target="_blank" >10.1016/j.ejphar.2025.178099</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Serotonin type 6 receptor inverse agonists and neutral antagonists inhibit defecation: relevance to intestinal motility disorders

Popis výsledku v původním jazyce

The serotonergic system plays a crucial role in numerous physiological processes in the central and peripheral nervous systems. In the gastrointestinal (GI) tract, serotonin has been implicated in the control of motility and visceral pain associated with irritable bowel syndrome (IBS). Here, we investigated the impact of blocking differently activated conformational states of the type 6 serotonin receptor (5-HT6) upon intestinal motility and diarrhea in both non-stressed and stressed mice. We evaluated full and partial inverse agonists (SB-399885 and PZ-1444, respectively), which target constitutively active serotonin 5-HT6 receptors and a neutral antagonist (CPPQ), which targets agonist-activated serotonin 5-HT6 receptors. We found that both inverse agonists and the neutral antagonist, administered intraperitoneally at the same doses similarly reduce defecation in physiological and stressful conditions. The effect of PZ-1444 was significantly potentiated by the co-administration of either SB-399885 or CPPQ. CPPQ co-administration did not attenuate the effect of SB-399885 and this combination did not produce significantly stronger inhibition of defecation than SB-399885 administered alone. Combining PZ-1444 and CPPQ produced the most pronounced effect on defecation. The present findings confirm the contribution of both constitutively active and agoniststimulated serotonin 5-HT6 receptors to intestinal motility and diarrhea and highlights the serotonin 5-HT6 receptor as a promising drug target for the treatment of functional GI disorders.

Název v anglickém jazyce

Serotonin type 6 receptor inverse agonists and neutral antagonists inhibit defecation: relevance to intestinal motility disorders

Popis výsledku anglicky

The serotonergic system plays a crucial role in numerous physiological processes in the central and peripheral nervous systems. In the gastrointestinal (GI) tract, serotonin has been implicated in the control of motility and visceral pain associated with irritable bowel syndrome (IBS). Here, we investigated the impact of blocking differently activated conformational states of the type 6 serotonin receptor (5-HT6) upon intestinal motility and diarrhea in both non-stressed and stressed mice. We evaluated full and partial inverse agonists (SB-399885 and PZ-1444, respectively), which target constitutively active serotonin 5-HT6 receptors and a neutral antagonist (CPPQ), which targets agonist-activated serotonin 5-HT6 receptors. We found that both inverse agonists and the neutral antagonist, administered intraperitoneally at the same doses similarly reduce defecation in physiological and stressful conditions. The effect of PZ-1444 was significantly potentiated by the co-administration of either SB-399885 or CPPQ. CPPQ co-administration did not attenuate the effect of SB-399885 and this combination did not produce significantly stronger inhibition of defecation than SB-399885 administered alone. Combining PZ-1444 and CPPQ produced the most pronounced effect on defecation. The present findings confirm the contribution of both constitutively active and agoniststimulated serotonin 5-HT6 receptors to intestinal motility and diarrhea and highlights the serotonin 5-HT6 receptor as a promising drug target for the treatment of functional GI disorders.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

N - Vyzkumna aktivita podporovana z neverejnych zdroju

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

EUROPEAN JOURNAL OF PHARMACOLOGY

ISSN

0014-2999

e-ISSN

1879-0712

Svazek periodika

1005

Číslo periodika v rámci svazku

OCT

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

6

Strana od-do

"178099-1"-"178099-6"

Kód UT WoS článku

001564576800008

EID výsledku v databázi Scopus

2-s2.0-105014393454