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 language | English |
|---|---|
| Pages (from-to) | 313-324 |
| Number of pages | 12 |
| Journal | Drug Development Research |
| Volume | 40 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 1997 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Pharmacology of 2-cyclohexylmethylidenehydrazinoadenosine (WRC-0470), a novel, short-acting adenosine A(2A) receptor agonist that produces selective coronary vasodilation
AU - Martin, Pauline L.
AU - Barrett, Richard J.
AU - Linden, Joel
AU - Abraham, William M.
PY - 1997/4/1
Y1 - 1997/4/1
N2 - 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.
AB - 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.
KW - A(2A)-agonist
KW - Adenosine
KW - Coronary blood flow
KW - Hemodynamics
KW - Pulmonary
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UR - http://www.scopus.com/inward/citedby.url?scp=0030880492&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1098-2299(199704)40:4<313::AID-DDR5>3.0.CO;2-M
DO - 10.1002/(SICI)1098-2299(199704)40:4<313::AID-DDR5>3.0.CO;2-M
M3 - Article
AN - SCOPUS:0030880492
VL - 40
SP - 313
EP - 324
JO - Drug Development Research
JF - Drug Development Research
SN - 0272-4391
IS - 4
ER -