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Pharmacology and toxicology of the A2A-adenosine receptor agonist 2- [(cyclohexylmethylene)hydrazino]adenosine (MRE-0470) in the rat

✍ Scribed by Pauline L. Martin; R.J. Barrett; A. Sykes; D.A. Droppleman; K.F. Wright; D. Mossem

Publisher: John Wiley and Sons
Year: 1997
Tongue: English
Weight: 207 KB
Volume: 42
Category: Article
ISSN: 0272-4391
DOI: 10.1002/(sici)1098-2299(199710)42:2<76::aid-ddr4>3.0.co;2-m

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✦ Synopsis

2-[(cyclohexylmethylene)hydrazino]adenosine (MRE-0470

) is an A 2A -adenosine receptor agonist that is a potent and selective coronary vasodilator. As part of a preclinical program, the pharmacology and toxicology of MRE-0470 have been studied in the rat.

In isolated vas deferens, MRE-0470 activated A 2A receptors (EC 50 = 6.3 nM) and at higher concentrations activated A 2B receptors (EC 50 = 13 µM). In atrial tissues, MRE-0470 produced negative inotropic and chronotropic actions through activation of A 1 receptors (EC 50 ~ 9 µM). MRE-0470 produced no positive inotropic or chronotropic actions in atrial or ventricular tissues. In anesthetized, reflex-blocked rats, MRE-0470 produced a decrease in hindquarter perfusion pressure (A 2 : ED 50 = 0.31 µg) and a decrease in heart rate (A 1 : ED 50 = 620 µg). In conscious rats, MRE-0470 (0.04-117 µg/kg bolus or 0.03-150 µg/kg/min infusion) produced dose-dependent hypotension and reflex tachycardia. MRE-0470 was rapidly eliminated from rat plasma with an elimination half-life of 10 min.

In toxicology studies, once per day 10-minute i.v. infusions of 3, 30, or 150 µg/kg/min MRE-0470 for 14 consecutive days resulted in no deaths and no changes in blood chemistry, but resulted in decreased motor activity and dose-related cardiomyopathy. Cardiomyopathy did not occur following single doses of MRE-0470. The incidence of this lesion is related to the duration of the repeated reflex tachycardia.

These studies show that MRE-0470 is a potent and selective A 2A receptor agonist in the rat. The observed toxicology of MRE-0470 is consistent with the exaggerated pharmacology due to high-dose drug administration. Drug Dev. Res. 42:76-85, 1997.

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