title: 1-[(Imidazolidin-2-yl)imino]-1H-indoles as new hypotensive agents: synthesis and in vitro and in vivo biological studies.
abstract: A series of 1-[(imidazolidin-2-yl)imino]-1H-indole analogues of hypotensive α2-AR agonists, 1-[(imidazolidin-2-yl)imino]-1H-indazoles, was synthesized and tested in vitro for their activities at α1- and α2-adrenoceptors as well as imidazoline I1and I2receptors. The most active 1-[(imidazolidin-2-yl)imino]-1H-indoles displayed high or moderate affinities for α1- and α2-adrenoceptors and substantial selectivity for α2-adrenoceptors over imidazoline-I1binding sites. The in vivo cardiovascular properties of indole derivatives 3 revealed that substitution at C-7 position of the indole ring may result in compounds with high cardiovascular activity. Among them, 7-fluoro congener 3g showed the most pronounced hypotensive and bradycardic activities in this experiment at a dose as low as 10 μg/kg i.v. Metabolic stability of the selected compounds of type 3 was determined using both in vitro and in silico approaches. The results indicated that these compounds are not vulnerable to rapid first-phase oxidative metabolism.
authors: Department of Chemical Technology of Drugs, Medical University of Gdańsk, Gdańsk, Poland.
authors: Anita
authors: A
authors: Kornicka
authors: Department of Chemical Technology of Drugs, Medical University of Gdańsk, Gdańsk, Poland.
authors: Aleksandra
authors: A
authors: Wasilewska
authors: Department of Organic Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors: Jarosław
authors: J
authors: Sączewski
authors: Department of Pharmacology, University of Alberta, Edmonton, Canada.
authors: Alan L
authors: AL
authors: Hudson
authors: Department of Pathophysiology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Konrad
authors: K
authors: Boblewski
authors: Department of Pathophysiology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Artur
authors: A
authors: Lehmann
authors: Department of Chemical Technology of Drugs, Medical University of Gdańsk, Gdańsk, Poland.
authors: Karol
authors: K
authors: Gzella
authors: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors: Mariusz
authors: M
authors: Belka
authors: Department of Chemical Technology of Drugs, Medical University of Gdańsk, Gdańsk, Poland.
authors: Franciszek
authors: F
authors: Sączewski
authors: Faculty of Chemistry, A. Mickiewicz University, Poznań, Poland.
authors: Maria
authors: M
authors: Gdaniec
authors: Department of Pathophysiology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Apolonia
authors: A
authors: Rybczyńska
authors: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors: Tomasz
authors: T
authors: Bączek
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006339:Heart Rate / Q000187:drug effects; D048289:Imidazolidines / Q000737:chemistry; D007211:Indoles / Q000737:chemistry*; D008297:Male; D011869:Radioligand Assay / Q000379:methods; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D048289:Imidazolidines; D007211:Indoles; D011942:Receptors, Adrenergic, alpha
keywords: alpha-adrenoceptor ligands; circulatory activity; imidazolines; indoles; metabolic stability