Relationship between activity and structure in derivatives of clonidine

Arzneimittelforschung. 1975 May;25(5):786-93.

Abstract

2-(2,6-Dichlorphenylamino)-(clonidine, Catapresan, Catapres), 2-(2,6-diethylphenylamino- (St 91), 2-(2-chloro-6-methylphenylamino)-, 2-(2-chloro-4-methylphenylamino)-, 2-(2-methyl-5-fluorophenylamino) -and 2-(2-chloro-3-methyl-phenylamino)-2-imidazoline were investigated in various pharmacological tests. 1. All substances increased blood pressure in spinal rats and initially in intact cats and dogs and increased the total peripheral resistance in the latter. As these compounds also showed mydriasis in conscious rats it has been concluded that these effects are due to stimulation of peripheral alpha-adrenoceptors. 2. With the exception of St 91 the substances lowered blood pressure following i.v. injection, they decreased heart rate in cats and dogs and the cardiac output in the latter. These four compounds also decreased heart rate in vagotomised and atropinised rats. It was concluded that these effects were due to a decrease in sympathetic activity of the CNS. 3. In anaesthetised rats with beta-adrenoceptor blockade by toliprolol, a blood pressure increase was elicited by i.v. injection of angiotensin and the resulting bradycardia was recorded as a measure of vagal reflex activity. Clonidine and three derivatives which have shown hypotensive activity facilitated the vagal cardiodepressor reflex; St 91 was inactive in this respect. It has been concluded that decrease in central sympathetic tone and increase in central vagal activity are linked together in these compounds. 4. St 91 did not lower blood pressure and did not facilitate vagal reflex bradycardia after i.v. injection in dogs, but was active after intracisternal injection. It has been concluded, therefore, that this compound is able to act on structures in the CNS like clonidine but these effects usually do not occur after systemic administration because of its poor ability to penetrate the blood-brain barrier. 5. All derivatives decreased gastric acid secretion. 6. All substances increased blood glucose levels and were sedative; St 91 was the least effective compound in both respects pointing to a central mediation of these effects. 7. The results show that clonidine and the derivatives tested have the same reaction pattern. 8. The relationship between the CNS mediated cardiovascular depression and the peripheral alpha-adrenergic stimulating potency in conjunction with the lipoid solubility have been discussed.

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Blood Pressure / drug effects
  • Cardiac Output / drug effects
  • Cats
  • Clonidine / analogs & derivatives*
  • Clonidine / pharmacology
  • Clonidine / toxicity
  • Dogs
  • Female
  • Gastric Acidity Determination
  • Heart Rate / drug effects
  • Male
  • Mice
  • Pupil / drug effects
  • Rats
  • Sleep / drug effects
  • Stimulation, Chemical
  • Structure-Activity Relationship
  • Vagotomy
  • Vagus Nerve / physiology
  • Vascular Resistance / drug effects

Substances

  • Blood Glucose
  • Clonidine