Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine Part 3.: Synthesis and pharmacological activity of 1-aryl-5,6(1H)dioxo-2,3-dihydroimidazo[1,2-α]imidazoles

Synthesis and pharmacological activity of 1-aryl-5,6(1H)dioxo-2,3-dihydroimidazo[12-a]imidazoles (D) are presented. The title compounds were obtained from 1-aryl-2-iminoimidazolidines (1) by cyclization reaction with oxalic acid derivatives-ethyl ester (2) or chloride (3). They were tested for pharmacological activity in animal and binding assay tests. With moderate acute toxic ity (LD50 similar to 200 mg kg(-1), i.p.), they exhibited significant analgesic and serotonergic activities as results of the 'writhing' and the 'hot plate' tests indicated, and reduced number of 'head twitch' episodes after 5-HTP (5-hydroxytryptophan) administration. Reversion of the antinociception produced in the 'writhing' test by small dose of naloxon (5 mg kg(-1)) can suggest an opioid-like mechanism of their analgesic activity. The probable receptor inhibition mechanism of their analgesic and serotonergic activity was confirmed in the binding assay tests (by radioligand displacement) toward the opioid mu and scrotonin 5-HT2 receptors. Additionally, they exhibited affinity toward the benzodiazepine (BZD) receptor as well, although in behavioral tests compounds did not produce any clear depressive effect on the central nervous system (CNS) of mice. Simple chemical structure of the title compounds, in comparison to other carbonyl derivatives of 1-aryl-2-iminoimidazolidine presented in this series of papers, underline very important role both of a hydrophobic moiety (aromatic ring) and polar groups (hydrogen-bond acceptors) in the serotonin receptor interaction. The coexistence of opioid-like, serotonergic and BZD receptor inhibition activity can be very interesting and can lead to creation of the novel group of antidepressants. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved.