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1-[(Imidazolidin-2-yl)imino]indazole. Highly α2/I1 Selective Agonist: Synthesis, X-ray Structure, and Biological Activity

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journal contribution
posted on 26.06.2008, 00:00 by Franciszek Sa̧czewski, Anita Kornicka, Apolonia Rybczyńska, Alan L. Hudson, Shu Sean Miao, Maria Gdaniec, Konrad Boblewski, Artur Lehmann
Novel benzazole derivatives bearing a (imidazolidin-2-yl)imino moiety at position 1 or 2 were synthesized by reacting 1-amino- or 2-aminobenzazoles with N,N′-bis(tert-butoxycarbonyl)imidazolidine-2-thione in the presence of HgCl2. Structures of 1-[(imidazolidin-2-yl)imino]indazole (marsanidine, 13a) and free base of the 4-Cl derivative 12e were confirmed by X-ray single crystal structure analysis. Compound 13a was found to be the selective α2-adrenoceptor ligand with α2-adrenoceptor/imidazoline I1 receptor selectivity ratio of 3879, while 1-[(imidazolidin-2-yl)imino]-7-methylindazole (13k) proved to be a mixed α2-adrenoceptor/imidazoline I1 receptor agonist with α2/I1 selectivity ratio of 7.2. Compound 13k when administered intravenously to male Wistar rats induced a dose-dependent decrease in mean arterial blood pressure (ED50 = 0.6 μg/kg) and heart rate, which was attenuated following pretreatment with α2A-adrenoceptor antagonist RX821002. Compound 13a may find a variety of medical uses ascribed to α2-adrenoceptor agonists, and its 7-methyl derivative 13k is a good candidate for development as a centrally acting antihypertensive drug.

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