Cardiovascular studies on different classes of soft drugs

A. Juhász, Nicholas Bodor

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Based on the inactive metabolite approach, three different classes of soft drugs were designed and synthesized. Their cardiovascular effects and duration of actions were studied in anesthetized male Sprague-Dawley rats compared to the traditional drugs. During the experiments ECG (leads II, aVF) and beat-to-beat blood pressure (BP) from the left carotid artery were recorded (except during the anticholinergic studies). The soft anticholinergic methoxycarbonylphenylcyclopentyl-N,N-dimethyltropinium methyl sulfate was as potent as atropine in the prevention of carbachol induced bradycardia; however, its action only lasted up to 15-30 min, compared to 2 h of that of atropine. In the isoproterenol-induced tachycardia model, while bufuralol at an i.v. dose of 3.8 μmol/kg (1 mg/kg) diminished heart rate (HR) for at least 2 h, the effects of the soft drugs lasted for only 30-40 min at equimolar doses. The methyl-, ethyl-, isopropyl-, and tert-butyl ester-analogs of the carboxylic acid metabolite of bufuralol showed the highest beta-blocking potencies (i.e., 30-50% of that of bufuralol). When these compounds were infused for 10 min at doses ranging from 2-4 μmol/kg/min, they caused a 20-40% decrease in HR and a 30-40% reduction in mean arterial pressure (MAP). These effects were similar to those elicited by esmolol at a dose of 20 μmol/kg/min in respect of the kinetics and in the extent of the reductions in heart rate and MAP. The isopropyl-, the sec- butyl-, and the neopentyl-esters of the acidic metabolite of amiodarone, with plasma hydrolytic half-lives of 60, 240 and 300 min, were tested in the benzene/adrenaline induced ventricular tachycardia (VT) model of the rat. All drugs were administered at a dose of 5 μmol/kg i.v. bolus immediately followed by an infusion at 15 μmol/kg/h for 2 h. It was found, that amiodarone resulted a complete suppression of VTs at 30 min after the start of drug administration, but its effect lasted up to the total course of the experiment (up to 180 min). On the contrary, both the sec-butyl and the isopropyl-analog resulted in complete suppression of VTs already during the first benzene/adrenaline challenge after drug administration (i.e., at 5 min). However, their effects disappeared between 15 and 30 min after discontinuation of the drug infusions in accordance with the enzymatic inactivation (ester hydrolysis) of these soft drugs. All these three classes of soft cardioactive drugs are good examples for highly potent but short acting drugs whose side effects might also be reduced via the retrometabolism based drug design.

Original languageEnglish
Pages (from-to)228-238
Number of pages11
JournalPharmazie
Volume55
Issue number3
Publication statusPublished - 2000

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Pharmaceutical Preparations
Metabolites
Esters
Amiodarone
Heart Rate
Cholinergic Antagonists
Benzene
Atropine
Epinephrine
Arterial Pressure
Rats
Drug infusion
Drug Design
Carbachol
Bradycardia
Ventricular Tachycardia
Carboxylic Acids
Drug-Related Side Effects and Adverse Reactions
Blood pressure
Isoproterenol

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

Cardiovascular studies on different classes of soft drugs. / Juhász, A.; Bodor, Nicholas.

In: Pharmazie, Vol. 55, No. 3, 2000, p. 228-238.

Research output: Contribution to journalArticle

Juhász, A & Bodor, N 2000, 'Cardiovascular studies on different classes of soft drugs', Pharmazie, vol. 55, no. 3, pp. 228-238.
Juhász, A. ; Bodor, Nicholas. / Cardiovascular studies on different classes of soft drugs. In: Pharmazie. 2000 ; Vol. 55, No. 3. pp. 228-238.
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