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

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.

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 after stress in male and female mice. Drug effects were assayed using behavioral paradigms. Patch clamp electrophysiology was used to determine the effect of drug on glutamatergic activity in hippocampal Cornu Ammonis 3 (CA3).

Prophylactic administration of DL5, DL7, or DL8 was effective at reducing stress-induced maladaptive behaviors in male and female mice; DL7 and DL8 were effective when administered after stress. When administered following learned helplessness (LH), DL7 reduced behavioral despair and increased c-Fos in the dentate gyrus (DG) and CA3. All novel compounds attenuated large-amplitude AMPA receptor-mediated bursts in ventral CA3 (vCA3). In aged male mice, prophylactic DL7 reduced behavioral despair.

These results characterize novel 5-HT₄R-targeting compounds for stress-induced psychiatric disease with the potential to address unmet needs in adult and aged patients with stress-induced psychiatric illness. Future work will characterize their mechanism of action with the goal of clinical development.