Antidepressant-like activity of the phenylpiperazine pyrrolidin-2-one derivatives in mice

The present study was designed to investigate the central nervous system activity of 23 novel phenylpiperazine pyrrolidin-2-one derivatives. These compounds had marked antiarrhythmic and hypotensive activities and revealed affinity for alpha(1)- and alpha(2)-adrenoceptors. These effects may be related to their alpha-adrenolytic properties. We assessed their antidepressant-like effect in the forced swimming test, influence of spontaneous locomotor activities and binding to 5-HT1A and 5-HT2 receptors. Our study demonstrated the strong antidepressant-like activity of compound EP-65 in the forced swimming test. The effect of EP-65 was stronger than results obtained with the classical antidepressants imipramine and mianserin. Other compounds, EP-41, EP-42, EP-44, EP-47, EP-48, EP-49, EP-50, EP-62, EP-66, EP-70, EP-75 and EP-76, showed significantly weaker activities in this test. Compound EP-42 showed the strongest affinity for 5-HT1A (K-i= 24.5 nM), and compound EP-50 showed the strongest affinity for the 5-HT2 receptor (K-i = 109.1 nM). All tested compounds significantly suppressed the spontaneous locomotor activity of mice. Currently, it is not possible to determine which mechanisms are involved in the witnessed antidepressant-like activity of novel phenylpiperazine pyrrolidin-2-one derivatives.