2-Phenyl-3-(Phenylselanyl)Benzofuran As a Promising Antidepressant Candidate: Mechanistic Insights Into Nitrergic Modulation and Subchronic Efficacy and Safety Profiling.

The compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1), a selenium-containing molecule based on a benzofuran scaffold, has shown antidepressant-like effects. This study investigated the involvement of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, the efficacy of subchronic treatment in male Swiss mice, and computational analyses. Acute SeBZF1 administration (50 mg/kg, i.g.) showed antidepressant-like effects in the tail suspension test (TST). These effects were reversed by pretreatment with L-arginine (a NO precursor, 750 mg/kg, intraperitoneal, i.p.) or sildenafil (a phosphodiesterase-5 inhibitor, 5 mg/kg, i.p.), suggesting NO-cGMP pathway involvement. A subeffective dose of SeBZF1 (1 mg/kg, i.g.) elicited synergistic antidepressant-like effects when combined with N(ω)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase (NOS) inhibitor, 10 mg/kg, i.p.) or 7-nitroindazole (a specific neuronal NOS inhibitor, 30 mg/kg, i.p.). Furthermore, methylene blue (an inhibitor of NOS and soluble guanylate cyclase (sGC), 10 mg/kg, i.p.) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, a sGC inhibitor, 30 pmol/site, intracerebroventricular), both soluble guanylate cyclase (sGC) inhibitors, enhanced the subeffective SeBZF1 dose. Subchronic SeBZF1 treatment (1 mg/kg, i.g., for 35 days) significantly produced antidepressant-like action without causing weight loss or organ damage. Biochemical analysis revealed reduced nitrate/nitrite levels in the prefrontal cortex and hippocampus, indicating modulation of NO signaling. Molecular docking suggested interactions between SeBZF1 and NOS isoforms, while pharmacokinetic analysis suggested brain penetration and absence of overt toxicity. The present study concludes that SeBZF1 exhibits antidepressant-like effects through the NO-cGMP pathway, is effective at low subchronic doses, and displays favorable pharmacokinetic and safety profiles, supporting its potential as a novel antidepressant candidate.