Pharmacology of 2-cyclohexylmethylidenehydrazinoadenosine (WRC-0470), a novel, short-acting adenosine A2A receptor agonist that produces selective coronary vasodilation
✍ Scribed by Pauline L. Martin; Richard J. Barrett; Joel Linden; William M. Abraham
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 225 KB
- Volume
- 40
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
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 2Areceptors. 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 A 1 , A 2B , or A 3 adenosine receptors. In guinea pig isolated tissues, WRC-0470 was a potent coronary vasodilator (A 2A : A 50 = 1.5 nM) but was a weak negative inotropic or chronotropic agent (A 1 : A 50 = 40-140 µM) and was a weak vasodilator in the aorta (A 2B : A 50 = 49 µM). WRC-0470 bound to human A 1 , A 2A , A 2B , and A 3 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 × 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 A 1 , A 2B , and A 3 receptors it is predicted that WRC-0470 will produce fewer side effects clinically than does ADO.