title: Circulatory effect of TCS-80, a new imidazoline compound, in rats.
abstract: 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 I1-imidazoline receptors and the lowest α2/I1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α2-adrenergic and I1-imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α2-adrenergic and/or I1-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 α2-adrenoceptor antagonist, RX821002, or nonselective α2-adrenergic/I1-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.
  
  
  CONCLUSIONS
  Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the α2-adrenergic and I1-imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I1-imidazoline receptors than by the α2-adrenergic ones.
authors.affiliation: Department of Pathophysiology, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Boblewski
authors.affiliation: Department of Pathophysiology, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Lehmann
authors.affiliation: Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Sączewski
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Sączewski
authors.affiliation: Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Anita
authors.initials: A
authors.lastname: Kornicka
authors.affiliation: Department of Pathophysiology, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Marchwińska
authors.affiliation: Department of Pathophysiology, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland. Electronic address: aryb@gumed.edu.pl.
authors.forename: Apolonia
authors.initials: A
authors.lastname: Rybczyńska
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D007022:Hypotension; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D048289:Imidazolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D054755:Imidazoline Receptors / Q000187:drug effects; D048288:Imidazolines / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D007191:Indazoles / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects
chemical_list: C531076:1-((imidazolidin-2-yl)imino)indazole; D001572:Benzofurans; D007093:Imidazoles; D048289:Imidazolidines; D054755:Imidazoline Receptors; D048288:Imidazolines; D007191:Indazoles; D018341:Receptors, Adrenergic, alpha-2; C000620451:TCS-80; C058525:2-methoxyidazoxan; C062597:efaroxan; D019329:Idazoxan
keywords: Efaroxan; Hypotensive effect; Imidazoline compounds; Marsanidine; RX821002