Elena Hernández-Hernández, Sandra Ledesma-Corvi, Fernando Yáñez-Gómez, Neus Mateu-Mercader, Andrea Bagán, Carmen Escolano, M. Julia García-Fuster

DOI: https://doi.org/10.1007/s43440-025-00810-w

Background: The synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates provided novel compounds
with relevant affinities for imidazoline 2 (I2) receptors in human brain tissues. A selected compound, 12d, showed improved
cognitive and analgesic properties at the preclinical level through the modulation of I2 receptors, but its potential innovative
use as an antidepressant is still unknown.
Methods Male and female adult Sprague-Dawley rats were treated with 3 ip injections of compound 12d (10 or 20 mg/kg),
or vehicle (1 ml/kg DMSO), 24, 5, and 1 h prior to scoring its antidepressant-like efficacy under the stress of the forcedswim
test. Hippocampal neuroplasticity markers (i.e., FADD, p-ERK/ERK, mBDNF) were evaluated 24 h post-treatment
(and post-forced-swim test exposure).
Results: The novel results proved a sex-dependent efficacy of 12d, with dose-dependent antidepressant-like effects in adult
male rats, and an inefficacious response for females. Moreover, compound 12d did not alter any of the hippocampal markers
evaluated.
Conclusions: These results presented 12d as a novel therapeutic antidepressant candidate at the tested conditions, although
only for male rats, thus requiring further studies to better understand the observed sex disparities as well as its molecular
underpinnings. Moreover, compound 12d joins the list of other I2 receptor ligands with known antidepressant-like efficacy,
validating and strengthening this receptor as a target in this field for future drug development