Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine: part 2. Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazines.
Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo-[1,2-a][1,3,5]triazines (C) are presented. The title compounds were obtained from 1-arylimidazolinurea derivatives in cyclization reaction with difunctional carbonyl reagents--phosgene (method I) or carbonyldiimidazole (CDI) (method II). Their molecular structures were confirmed by the X-ray analysis of 1-phenyl-6-(4-chlorophenyl)-5,7(1H)-dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazine (C2) crystals. Compounds C exhibited significant depressive action on the central nervous system (CNS) of the laboratory animals, correlated with very low acute toxicity (LD(50) > 2000 mg kg(-1) i.p.), and showed antinociceptive activity in behavioural models. Reversion of this effect by small dose of naloxone (5 mg kg(-1)) can suggest opioid-like mechanism of antinociception produced by these and other carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Additionally, an effect on the serotonin neurotransmission pathway was also observed. The receptor mechanism of activity for investigated compounds was confirmed only for the opioid mu receptor in binding affinity assay test. Same tests performed for the serotonin 5-HT(2) and benzodiazepine BZD receptors showed no affinity for tested compounds. The opioid-like and serotonergic activities are similar to these described earlier for chain carbonyl 1-aryl-2-iminoimidazolidine derivatives containing urea moiety, mainly due to similar chemical structure, although compounds C are not able to adopt any of the higher energy conformations of urea derivatives. Rigid location of aromatic ring (Ar') at N6, acting as a spacer blocking any direct access to the carbonyl groups (e.g. through the hydrogen bonding), could be responsible for lack of affinity toward 5-HT(2) expressed in the binding assay test.
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D003292:Convulsants; D018360:Crystallography, X-Ray; D006591:Hexobarbital / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010433:Pentylenetetrazole; D011930:Reaction Time / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A; D011963:Receptors, GABA-A / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012890:Sleep / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology*
D000701:Analgesics, Opioid; D003292:Convulsants; D006993:Hypnotics and Sedatives; D007202:Indicators and Reagents; D044402:Receptor, Serotonin, 5-HT2A; D011963:Receptors, GABA-A; D017450:Receptors, Opioid, mu; D011985:Receptors, Serotonin; D014227:Triazines; D006591:Hexobarbital; D006916:5-Hydroxytryptophan; D010433:Pentylenetetrazole