Pharmacology of 2-cyclohexylmethylidenehydrazinoadenosine (WRC-0470), a novel, short-acting adenosine A(2A) receptor agonist that produces selective coronary vasodilation

Pauline L. Martin, Richard J. Barrett, Joel Linden, William M. Abraham

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Intravenous adenosine (ADO) is used clinically to produce coronary vasodilation during myocardial perfusion imaging studies. The coronary vasodilation produced by ADO is due to activation of A(2A)-receptors. An analogue of ADO WRC-0470 was developed that was selective for the A(2A)-receptor. The present studies were designed to determine whether WRC-0470 could produce selective coronary vasodilation but be devoid of the side effects that ADO possesses due to activation of A1, A(2B), or A3 adenosine receptors. In guinea pig isolated tissues, WRC-0470 was a potent coronary vasodilator (A(2A): A50 = 1.5 nM) but was a weak negative inotropic or chronotropic agent (A1: A50 = 40-140 μM) and was a weak vasodilator in the aorta (A(2B): A50 = 49 μM). WRC-0470 bound to human A1, A(2A), A(2B) and A3 receptors with affinities of 48 μM, 270 nM, 430 μM, and 903 nM, respectively. Intravenous infusion of WRC-0470 (0.1-0.6 μg/kg/min x 10 min) to anesthetized and conscious dogs produced coronary vasodilation at doses that produced little or no systemic hypotension. Only at infusion doses in excess of 0.6 μg/kg/min was a significant decrease in blood pressure and a decrease in left ventricular pressure observed. WRC-0470 had no consistent or significant effect on heart rate, PR interval, QRS interval, or QT interval. WRC-0470 was rapidly cleared from dog plasma with an elimination half-life of 6 min. In an allergic sheep model of asthma, the clinically predicted dose of WRC-0470 (≤0.6 μg/kg/min) produced no significant increase in lung resistance whereas the clinical dose of ADO (140 μg/kg/min) produced a 100% increase in lung resistance. WRC-0470 is a short-acting A(2A) selective ADO agonist that produces selective coronary vasodilation in the dog. Because WRC-0470 is a weak agonist at A1, A(2B) and A3 receptors it is predicted that WRC-0470 will produce fewer side effects clinically than does ADO.

Original languageEnglish
Pages (from-to)313-324
Number of pages12
JournalDrug Development Research
Volume40
Issue number4
DOIs
StatePublished - Apr 1 1997
Externally publishedYes

Fingerprint

Adenosine A2A Receptors
Vasodilation
Pharmacology
Adenosine
Dogs
Vasodilator Agents
binodenoson
Adenosine A2B Receptors
Adenosine A3 Receptors
Chemical activation
Lung
Myocardial Perfusion Imaging
Blood pressure
Ventricular Pressure
Intravenous Infusions
Hypotension
Half-Life
Aorta
Sheep
Guinea Pigs

Keywords

  • A(2A)-agonist
  • Adenosine
  • Coronary blood flow
  • Hemodynamics
  • Pulmonary

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Pharmacology of 2-cyclohexylmethylidenehydrazinoadenosine (WRC-0470), a novel, short-acting adenosine A(2A) receptor agonist that produces selective coronary vasodilation. / Martin, Pauline L.; Barrett, Richard J.; Linden, Joel; Abraham, William M.

In: Drug Development Research, Vol. 40, No. 4, 01.04.1997, p. 313-324.

Research output: Contribution to journalArticle

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abstract = "Intravenous adenosine (ADO) is used clinically to produce coronary vasodilation during myocardial perfusion imaging studies. The coronary vasodilation produced by ADO is due to activation of A(2A)-receptors. An analogue of ADO WRC-0470 was developed that was selective for the A(2A)-receptor. The present studies were designed to determine whether WRC-0470 could produce selective coronary vasodilation but be devoid of the side effects that ADO possesses due to activation of A1, A(2B), or A3 adenosine receptors. In guinea pig isolated tissues, WRC-0470 was a potent coronary vasodilator (A(2A): A50 = 1.5 nM) but was a weak negative inotropic or chronotropic agent (A1: A50 = 40-140 μM) and was a weak vasodilator in the aorta (A(2B): A50 = 49 μM). WRC-0470 bound to human A1, A(2A), A(2B) and A3 receptors with affinities of 48 μM, 270 nM, 430 μM, and 903 nM, respectively. Intravenous infusion of WRC-0470 (0.1-0.6 μg/kg/min x 10 min) to anesthetized and conscious dogs produced coronary vasodilation at doses that produced little or no systemic hypotension. Only at infusion doses in excess of 0.6 μg/kg/min was a significant decrease in blood pressure and a decrease in left ventricular pressure observed. WRC-0470 had no consistent or significant effect on heart rate, PR interval, QRS interval, or QT interval. WRC-0470 was rapidly cleared from dog plasma with an elimination half-life of 6 min. In an allergic sheep model of asthma, the clinically predicted dose of WRC-0470 (≤0.6 μg/kg/min) produced no significant increase in lung resistance whereas the clinical dose of ADO (140 μg/kg/min) produced a 100{\%} increase in lung resistance. WRC-0470 is a short-acting A(2A) selective ADO agonist that produces selective coronary vasodilation in the dog. Because WRC-0470 is a weak agonist at A1, A(2B) and A3 receptors it is predicted that WRC-0470 will produce fewer side effects clinically than does ADO.",
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