Circulatory Activities of Some 2-Imidazoline Derivatives in Wistar Rats

Abstract

Background 2-aryliminoimidazolines constitute a valuable class of centrally acting antihypertensive drugs. The aim of our studies was to evaluate effects of some analogues of clonidine and lofexidine on the arterial blood pressure and heart rate in Wistar rats following i.v. administration.
Material and methods Effects of a-hydroxy (1a-g) and 2-amino (2a-d) analogues of clonidine and N-benzyl-N- -(4,5-dihydro-1H-imidazol-2-yl)-methoxylamine (3) on the mean arterial blood pressure and heart rate were determined in normotensive, male Wistar rats weighting 220–370 g. The experiments were performed using animals anaesthetized with urethane and tracheotomized.
Results Compounds 1a-g showed hypotensive activity accompained by a positive chronotropic effect with 1b being the most active (ED50 = 0,17 and 0,145 mg/kg respectively). Among the 2-amino-phenyliminoimidazolines of type 2, the more hydrophilic 2a and 2b exhibited relatively weak hypotensive effects, while the more hydrophobic analogues 2c and 2d were shown to possess remarkable hypertensive activities at doses 0,25 mg/kg. X-ray crystal structure analysis of the thiocyanate salt 2e confirmed geometrical features required for good ligand interaction at the a2-adrenergic receptors. On the other hand, N-benzyl-N-(4,5-dihydro-1H-imidazol-2-yl)-methoxylamine 3was not active at doses up to 2 mg/kg.
Conclusions The introduction of the hydroxyl group on the exocyclic nitrogen atom of 2-aryliminoimidazolines afforded compounds retaining much of the hypotensive activity. On the other hand, cardiovascular activity of the analogues containing 2-amino substituent at the phenyl ring depends strongly on their lipophilic character. It can be presumed that penetration of the more lipophilic 2c and 2d into the CNS enables these compounds to block a2-adrenergic receptors which results in an increased blood pressure.