title: Derivatives of pyrrolo[3,4-d]pyridazinone, a new class of analgesic agents.
abstract: A series of N2-{2-[4-aryl(benzyl)-1-piperazinyl(piperidinyl)]ethyl}pyrrolo[3,4-d]pyridazinones 4 and related derivatives 5 were synthesized as potential analgesic agents. The structures of the new compounds were elucidated by micro, spectral and X-ray analysis. Analgesic activity of the compounds was investigated in the phenylbenzoquinone induced 'writhing' and 'hot plate' test in mice and at radioligand binding assay. At 'writhing' test all compounds, without exception, were more active than acetylsalicylic acid (ASA) with ED(50) values ranging from 0.04 to 11 mg/kg (i.p.) (ED(50) for ASA--39.15 mg/kg). Analgesic effect at the 'hot plate' test was observed for three compounds 4c,e,f at the dose 3-5 times higher then that of morphine (ED(50)-3.39 mg/kg). At radioligand binding assay of 4c,e,f only compound 4f exhibited affinity for the μ-opioid receptors similar to that of Tramadol. The acute toxicity of the pyrrolopyridazinones 4, 5 were also studied and non toxic effect was observed at the 2000 mg/kg (5a 1420 mg/kg) i.p. dose level. On the basis of the available pharmacological data S-A relationship is discussed. The preferred conformational characteristic of 4, taken 4c as an example, was also described.
authors.affiliation: Department of Chemistry of Drugs, Wrocław Medical University, 1 Tamka Str., Wrocław 50-137, Poland.
authors.forename: Wiesław
authors.initials: W
authors.lastname: Malinka
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Redzicka
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jastrzębska-Więsek
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dybała
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Karczmarzyk
authors.forename: Zofia
authors.initials: Z
authors.lastname: Urbańczyk-Lipkowska
authors.forename: Przemysław
authors.initials: P
authors.lastname: Kalicki
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D018360:Crystallography, X-Ray; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D011724:Pyridazines; D011758:Pyrroles; C500991:pyrrolo(3,4-d)pyridazinone