Novel, small molecules targeting the 5-HT₄ receptor protect against stress-induced maladaptive behavior with efficacy across age.

ABSTRACT:

Background

Stress is a risk factor for developing psychiatric disorders, including major depressive disorder (MDD). Compounds targeting the serotonin type 4 receptor (5-HT₄R) hold promise as novel rapid-acting treatments of mood disorders. However, a lack of selectivity and numerous side effects have been limiting factors for their clinical use. Here, we developed and characterized novel-composition 5-HT₄R compounds in mouse models of stress.

Methods

Three 5-HT₄R-targeting compounds were designed and synthesized based on PF-04995274, a high-affinity 5-HT₄R ligand reported to be a partial agonist. G-protein assays were utilized to characterize molecular activity. Saline, PF-04995274, or a novel compound were administered before or a

SUBMITTER: Ravenelle R 

PROVIDER: S-EPMC12632445 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature