Circulatory effect of TCS-80, a new imidazoline compound, in rats

Background: Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1H-indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I-1-imidazoline receptors and the lowest alpha(2)/I-1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through alpha(2)-adrenergic and I-1-imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether alpha(2)-adrenergic and/or I-1-imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats. Methods: Anesthetized rats were infused iv with the tested compounds and selective alpha(2)-adrenoceptor antagonist, RX821002, or nonselective alpha(2)-adrenergic/I-1-imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment. Results: Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only. Conclusion: Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the alpha(2)-adrenergic and I-1-imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I-1-imidazoline receptors than by the alpha(2)-adrenergic ones. (C) 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.