title: Synthesis, central nervous system activity and structure-activity relationship of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea and products of their cyclization.
abstract: A series of 20 N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea and products of their cyclization was designed as compounds having double antinociceptive and serotoninergic activity. Ethyl {[(1-arylimidazolidin-2-ylidene)carbamoyl]amino}acetates were prepared from 1-aryl-4,5-dihydro-1H-imidazol-2-amines and ethyl isocyanatoacetate, and then converted with ammonia solution to 2-{[(1-phenylimidazolidin-2-ylidene)carbamoyl]amino}acetamides. Both series of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneureas were subjected to cyclization to respective imidazo[1,2-a][1,3,5]triazines. Chain and cyclic compounds bearing ester moiety affected spontaneous locomotor activity, body temperature of mice as well as showed antinociceptive and serotoninergic activity. Interestingly, their antinociceptive activity was not reversed by naloxone, thus it is not mediated through the opioid system. Chain and cyclic compounds bearing amide moiety were devoid of central nervous system (CNS) activity which may be attributed to unfavorably low lipophilicity (connected with too high polar surface area and too small molecular volume) and poor blood-brain barrier permeation properties.
authors: a Faculty of Pharmacy with Division of Medical Analytics, Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab , Medical University of Lublin , Lublin , Poland .
authors: Elżbieta
authors: E
authors: Szacoń
authors: Marzena
authors: M
authors: Rządkowska
authors: Agnieszka A
authors: AA
authors: Kaczor
authors: Ewa
authors: E
authors: Kędzierska
authors: Antonina
authors: A
authors: Mazur
authors: Sylwia
authors: S
authors: Fidecka
authors: Dariusz
authors: D
authors: Matosiuk
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018490:Serotonin Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000700:Analgesics; D048288:Imidazolines; D018490:Serotonin Agents; D014508:Urea
keywords: 1-aryl-4; 5-dihydro-1H-imidazol-2-amines; antinociceptive compounds; central nervous system (CNS) activity; imidazo[1,2-a][1,3,5]triazines