1-[(Imidazolidin-2-yl)imino]indazole. Highly alpha 2/I1 selective agonist: synthesis, X-ray structure, and biological activity.
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 HgCl 2. 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 alpha 2-adrenoceptor ligand with alpha 2-adrenoceptor/imidazoline I 1 receptor selectivity ratio of 3879, while 1-[(imidazolidin-2-yl)imino]-7-methylindazole ( 13k) proved to be a mixed alpha 2-adrenoceptor/imidazoline I 1 receptor agonist with alpha 2/I 1 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 microg/kg) and heart rate, which was attenuated following pretreatment with alpha 2A-adrenoceptor antagonist RX821002. Compound 13a may find a variety of medical uses ascribed to alpha 2-adrenoceptor agonists, and its 7-methyl derivative 13k is a good candidate for development as a centrally acting antihypertensive drug.
Saczewski
Franciszek
F
Department of Chemical Technology of Drugs and Department of Pathophysiology, Medical University of Gdańsk, 80-416 Gdańsk, Poland. saczew@amg.gda.pl
Kornicka
Anita
A
Rybczyńska
Apolonia
A
Hudson
Alan L
AL
Miao
Shu Sean
SS
Gdaniec
Maria
M
Boblewski
Konrad
K
Lehmann
Artur
A
D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D006339:Heart Rate / Q000187:drug effects; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054755:Imidazoline Receptors / Q000819:agonists* / Q000737:chemistry; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics
C531077:1-((imidazolidin-2-yl)imino)-7-methylindazole; C531076:1-((imidazolidin-2-yl)imino)indazole; D058647:Adrenergic alpha-2 Receptor Agonists; D000959:Antihypertensive Agents; D048289:Imidazolidines; D054755:Imidazoline Receptors; D007191:Indazoles; D018341:Receptors, Adrenergic, alpha-2; C410887:imidazoline I1 receptors