1-[(Imidazolidin-2-yl)imino]-1H-indoles as new hypotensive agents: synthesis and in vitro and in vivo biological studies.

A series of 1-[(imidazolidin-2-yl) imino]-1H-indole analogues of hypotensive alpha(2)-AR agonists, 1-[(imidazolidin-2-yl) imino]-1H-indazoles, was synthesized and tested in vitro for their activities at alpha(1)-and alpha(2)-adrenoceptors as well as imidazoline I-1 and I-2 receptors. The most active 1-[(imidazolidin-2-yl) imino]-1H-indoles displayed high or moderate affinities for alpha(1)-and alpha(2)-adrenoceptors and substantial selectivity for alpha(2)-adrenoceptors over imidazoline-I-1 binding 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 mu g/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.