title: 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-a]imidazoles.
abstract: Synthesis and pharmacological activity of 1-aryl-5,6(1H)dioxo-2,3-dihydroimidazo[1,2-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 toxicity (LD(50) approximately 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 serotonin 5-HT(2) 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 co-existence of opioid-like, serotonergic and BZD receptor inhibition activity can be very interesting and can lead to creation of the novel group of antidepressants.
authors.affiliation: Department of Synthesis and Technology of Drugs, Medical University in Lublin, Staszica 6, 20-081 Lublin, Poland. darek@eskulap.am.lublin.pl
authors.forename: Dariusz
authors.initials: D
authors.lastname: Matosiuk
authors.forename: Sylwia
authors.initials: S
authors.lastname: Fidecka
authors.forename: Lucyna
authors.initials: L
authors.lastname: Antkiewicz-Michaluk
authors.forename: Izabela
authors.initials: I
authors.lastname: Dybala
authors.forename: Anna E
authors.initials: AE
authors.lastname: Koziol
mesh_terms: D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007928:Lethal Dose 50; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D011869:Radioligand Assay; D011930:Reaction Time / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D018490:Serotonin Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D007093:Imidazoles; D011963:Receptors, GABA-A; D017450:Receptors, Opioid, mu; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D006916:5-Hydroxytryptophan