Antidepressant-like activity of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and evidence for the involvement of serotonin receptor subtypes in their mechanism of action.

Since serotonin (5-HT) is strongly involved in the etiology and pathophysiology of depression, the development of new antidepressants is still based on the serotonergic system. The complexity of serotonergic system provides an opportunity for the development of compounds with multiple and complementary mechanism of action. This study describes serotonin receptor profile, functional characterization, and pharmacological in vivo evaluation of new aroxyalkyl derivatives of 2-methoxyphenylpiperazine. The obtained results allowed for the identification of compound 3, (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride), a partial 5-HT1A receptor agonist, and 5-HT2A receptor antagonist, with high affinity toward 5-HT7 receptors, showing antidepressant- and anxiolytic-like properties. Moreover, 5-HT1A receptor activation is crucial for the antidepressant-like activity of compound 3. The rest of the compounds (except compounds 1 and 9) showed antidepressant but not anxiolytic-like properties, which did not result from 5-HT1A receptors activation. Furthermore, the compounds are 5-HT1A and weak 5-HT3 receptors antagonists, and some of them 5-HT2A antagonists. Moreover, none of the studied compounds impaired motor coordination at antidepressant-like doses. Since the studied compounds exhibited activity in behavioral assays and interacted with various receptors, the results of our experiments are very promising and require further studies.