title: Antinociceptive, anti-inflammatory and smooth muscle relaxant activities of the pyrrolo[3,4-d]pyridazinone derivatives: Possible mechanisms of action.
abstract: The aim of this study was to evaluate the analgesic as well as anti-inflammatory activities of the new pyrrolo[3,4-d]pyridazinone derivatives. Moreover, the present study attempted to assess some of the mechanisms involved in the pharmacological activity of these compounds. In the previous studies it was shown that these compounds were highly active in the phenylbenzoquinone-induced 'writhing syndrome' test and had much lower activity in the hot plate, which indicates that mainly peripheral mechanisms of analgesia are involved in their effects. In these extended studies the analgesic activity of two tested compounds (4c, 4f) was confirmed in some animal models of pain. The studied compounds showed a significant and dose-related antinociceptive effect in the models of pain induced by formalin, capsaicin and glutamic acid. Both compounds decreased the edema formation and one of them (4c) attenuated mechanical hyperalgesia in carrageenan-induced paw inflammation in rats. Furthermore, both compounds inhibited cell migration, plasma exudation and nociceptive reaction in zymosan A-induced mouse peritonitis. In the subsequent studies, including experiments on isolated organs (ileum, trachea, aorta), radioligand assays and biochemical tests, it was demonstrated that analgesic and anti-inflammatory effects of the investigated structures are largely due to their competitive antagonism for histamine H1 receptor. The influence on the level of cAMP in inflammatory cells (shown in RAW 264.7 macrophages) and subsequent inhibition of cytokine (TNFα, IL-1β) release can also be one of the important mechanisms of their action. Moreover some additional mechanisms may also be involved in the eventual analgesic effect of tested pyrrolo[3,4-d]pyridazinone derivatives.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, 9 Medyczna Str., 30-688 Kraków, Poland. Electronic address: szczepan.mogilski@uj.edu.pl.
authors.forename: Szczepan
authors.initials: S
authors.lastname: Mogilski
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, 9 Medyczna Str., 30-688 Kraków, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kubacka
authors.affiliation: Department of Chemistry of Drugs, Wrocław Medical University, 211 Borowska Str., 50-556 Wrocław, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Redzicka
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, 9 Medyczna Str., 30-688 Kraków, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kazek
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, 9 Medyczna Str., 30-688 Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Dudek
authors.affiliation: Department of Chemistry of Drugs, Wrocław Medical University, 211 Borowska Str., 50-556 Wrocław, Poland.
authors.forename: Wiesław
authors.initials: W
authors.lastname: Malinka
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, 9 Medyczna Str., 30-688 Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D045442:Rotarod Performance Test
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006634:Histamine H1 Antagonists; D011724:Pyridazines; D011758:Pyrroles
keywords: Histamine; Inflammation; Pain; Pyridazinone; Smooth muscle