PHARMACOLOGY AND TOXICOLOGY OF THE A(2A)-ADENOSINE RECEPTOR AGONIST 2-[(CYCLOHEXYLMETHYLENE)HYDRAZINO]ADENOSINE (MRE-0470) IN THE RAT

2-[(cyclohexylmethylene)hydrazino]adenosine (MRE-0470) is an A(2A)-ade nosine receptor agonist that is a potent and selective coronary vasodi lator. As part of a preclinical program, the pharmacology and toxicolo gy of MRE-0470 have been studied in the rat. In isolated vas deferens, MRE-0470 activated A(2A) receptors (EC50 = 6.3 nM) and at higher conc entrations activated A(2B) receptors (EC50 = 13 mu M). In atrial tissu es, MRE-0470 produced negative inotropic and chronotropic actions thro ugh activation of A(1) receptors (EC50 similar to 9 mu M). MRE-0470 pr oduced no positive inotropic or chronotropic actions in atrial or vent ricular tissues. In anesthetized, reflex-blocked rats, MRE-0470 produc ed a decrease in hindquarter perfusion pressure (A(2): ED50 = 0.31 mu g) and a decrease in heart rate (A(1): ED50 = 620 mu g). In conscious rats, MRE-0470 (0.04-117 mu g/kg bolus or 0.03-150 mu g/kg/min infusio n) produced dose-dependent hypotension and reflex tachycardia. MRE-047 0 was rapidly eliminated from rat plasma with an elimination half-life of 10 min. In toxicology studies, once per day 10-minute i.v. infusio ns of 3, 30, or 150 mu g/kg/min MRE-0470 for 14 consecutive days resul ted in no deaths and no changes in blood chemistry, but resulted in de creased motor activity and dose-related cardiomyopathy. Cardiomyopathy did not occur following single doses of MRE-0470. The incidence of th is lesion is related to the duration of the repeated reflex tachycardi a. These studies show that MRE-0470 is a potent and selective A(2A) re ceptor agonist in the rat. The observed toxicology of MRE-0470 is cons istent with the exaggerated pharmacology due to high-dose drug adminis tration. (C) 1997 Wiley-Liss, Inc.