Abstract
This study was aimed to synthesize novel 2-(2-bromophenyl)-N-phenethylacetamides and benzylisoquinoline (BIQ) derivatives to be evaluated as antidepressant-like agents in mice. The N-phenethylacetamides derivatives were synthesized by coupling aromatic amides to the backbone of 2-bromophenylacetyl chloride. The synthesis of BIQ was achieved by the reaction between synthesized phenethylacetamides and 2-chloropyridine. The structures of the compounds were established mainly by 1D and 2D NMR spectra. Those compounds obtained with moderate to good yields were evaluated as antidepressant-like agents in the forced swimming test and the open field paradigms in mice. The possible mechanism of those active derivatives was explored by antagonist experiments in combination with p-chloro-phenylalanine methyl ester, reserpine, sulpiride, and dopamine D1 antagonist SCH23390. Also, MAO A and B inhibition assay were performed. Docking studies of the human dopamine D3 receptor with the most active compound was performed. The results showed that the (2-bromophenyl) (3,4-dihydroisoquinoline-1-yl)methanone (4a) presented the most potent antidepressant-like effects without modifying the ambulatory activity of experimental mice. Antagonist experiments showed that 4a acted on the serotonergic and dopaminergic receptors. Docking studies indicated a strong affinity of the human dopamine D3 receptor for 4a. Our results showed that benzylisoquinoline 4a has an antidepressant-like effect that is mediated at least in part by an interaction with the presynaptic serotonin receptors, and dopaminergic D1, D2, and D3, receptors. This study highlights the pharmacological potential of halogenated BIQ’s in the treatment of some depressive disorders.