title: Fluorinated analogues of marsanidine, a highly α2-AR/imidazoline I1 binding site-selective hypotensive agent. Synthesis and biological activities.
abstract: The aim of these studies was to establish the influence of fluorination of the indazole ring on the pharmacological properties of two selective α2-adrenoceptor (α2-AR) agonists: 1-[(imidazolidin-2-yl)imino]-1H-indazole (marsanidine, A) and its methylene analogue 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (B). Introduction of fluorine into the indazole ring of A and B reduced both binding affinity and α2-AR/I1 imidazoline binding site selectivity. The most α2-AR-selective ligands were 6-fluoro-1-[(imidazolidin-2-yl)imino]-1H-indazole (6c) and 7-fluoro-1-[(imidazolidin-2-yl)imino]-1H-indazole (6d). The in vivo cardiovascular properties of fluorinated derivatives of A and B revealed that in both cases the C-7 fluorination leads to compounds with the highest hypotensive and bradycardic activities. The α2-AR partial agonist 6c was prepared as a potential lead compound for development of a radiotracer for PET imaging of brain α2-ARs.
authors.affiliation: Department of Chemical Technology of Drugs, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland. Electronic address: alwas@gumed.edu.pl.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wasilewska
authors.affiliation: Department of Chemical Technology of Drugs, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Sączewski
authors.affiliation: Department of Pharmacology, University of Alberta, 947 Medical Sciences Building, Edmonton T6G 2H7, Canada.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Hudson
authors.affiliation: Department of Pharmacology, University of Alberta, 947 Medical Sciences Building, Edmonton T6G 2H7, Canada.
authors.forename: Mehnaz
authors.initials: M
authors.lastname: Ferdousi
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Turku University Hospital, Fl-20014 Turku, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Turku University Hospital, Fl-20014 Turku, Finland.
authors.forename: Jonne M
authors.initials: JM
authors.lastname: Laurila
authors.affiliation: Department of Pathophysiology, Medical University of Gdańsk, Dębinki 7, Building 27, 80-211 Gdańsk, Poland.
authors.forename: Apolonia
authors.initials: A
authors.lastname: Rybczyńska
authors.affiliation: Department of Pathophysiology, Medical University of Gdańsk, Dębinki 7, Building 27, 80-211 Gdańsk, Poland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Boblewski
authors.affiliation: Department of Pathophysiology, Medical University of Gdańsk, Dębinki 7, Building 27, 80-211 Gdańsk, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Lehmann
mesh_terms: D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D054879:Halogenation; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D048288:Imidazolines / Q000378:metabolism*; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: C531076:1-((imidazolidin-2-yl)imino)indazole; D000959:Antihypertensive Agents; D048289:Imidazolidines; D048288:Imidazolines; D007191:Indazoles; D018341:Receptors, Adrenergic, alpha-2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
keywords: Indazole; Marsanidine; Selectfluor; α(2)-Adrenoceptor