2-(N'-aralkylidenehydrazino)adenosines: potent and selective coronary vasodilators.

Abstract

This study aimed at the development of 2-(N'-aralkylidenehydrazino)adenosines as coronary vasodilators. The reaction of aromatic aldehydes or ketones with 2-hydrazinoadenosine in refluxing methanol formed the target compounds 2-27 as crystalline products in good yields. Two kinds of receptors mediate the actions of adenosine on the heart. Retardation of impulse conduction through the atrioventricular node, the negative dromotropic action, is an example of adenosine's action at an A1 receptor (A1AR) and coronary vasodilation reflects adenosine's action at an A2 receptor (A2AR). Accordingly, bioassays employing guinea pig heart Langendorff preparations assessed the selectivity of 2-27 as coronary vasodilators. Analogues 2-27 were weak negative dromotropic agents; the EC50 of the most active analogue, 2-[N'-(1-naphthylmethylene)hydrazino]-adenosine, 23, was 0.8 microM, several orders of magnitude less than many A1AR agonists. Some of the analogues were quite active coronary vasodilators; 2-(N'-benzylidenehydrazino)adenosine, 2, and several of its para-substituted derivatives, namely, the fluoro (7), methyl (13), methoxy (16), and tert-butylcarbonylethyl, 31, had EC50s for coronary vasodilation in the range 1.7-3.2 nM. The selectivity ratios, EC50 (negative dromotropic)/EC50 (coronary vasodilatory), of these five analogues ranged between 5100 (analogue 31) and 43,000 (analogue 2). Phenyl ring substitutions of other kinds or at other positions, replacement of the phenyl ring by other aryl or heteroaryl groups, or the replacement of the benzylic H by a methyl group lowered coronary vasoactivity significantly. The unselective adenosine receptor antagonist 8-(p-sulfophenyl)theophylline raised the EC50 of the negative dromotropic activities of 2, 16, and 2-[N'-(2-naphthylmethylene)hydrazino]adenosine, 24, by 3-, 18-, and 7-fold, and raised the EC50s of coronary vasoactivity by 11-, 3-, and 30-fold, respectively evidence that vasoactivity was receptor-mediated.

Pharmacological Stress Myocardial Perfusion Imaging With the Potent and Selective A 2A Adenosine Receptor Agonists ATL193 and ATL146e Administered by Either Intravenous Infusion or Bolus Injection

“…13 These compounds are thought to produce coronary artery dilatation by activating coronary artery A 2A receptors. 7,21 All of these compounds have limited selectivity for A 2A over A 3 receptors on the basis of radioligand binding assays. This selectivity may be underestimated in binding assays, owing to the fact that there are 2 affinity states of G protein-coupled receptors for agonists, and recombinant A 2A receptors are poorly coupled to G proteins and consequently, bind agonists selectively to the low-affinity receptor conformation.…”

Pharmacology of 2-cyclohexylmethylidenehydrazinoadenosine (WRC-0470), a novel, short-acting adenosine A2A receptor agonist that produces selective coronary vasodilation

“…Recent studies in the guinea pig heart have shown that 2-cyclohexylmethylidinehydrazino-adenosine (WRC-0470) is a highly potent coronary vasodilator that is 14,000-fold more potent at producing coronary vasodilation through activation of A 2A -receptors than it is at producing atrioventricular conduction delay through activation of A 1 -ADO receptors [Niiya et al, 1992]. In the present study, the pharmacological properties of WRC-0470 have been further investigated and compared to ADO in an attempt to determine whether WRC-0470 possesses the desired properties for use as a pharmacological agent in myocardial perfusion imaging.…”

Molecular modeling of adenosine receptors. The ligand binding site on the rat adenosine A2A receptor

“…Selective ligands to characterize the adenosine A 2A receptor have been scarce, unlike A 1selective ligands. Only quite recently truly A 2 selective agonists have become available (Francis et al, 1991;Ueeda et al, 1991aUeeda et al, , 1991bNiiya et al, 1992aNiiya et al, , 1992b, whereas A 2 selective antagonists were still lacking. With the disclosure of 8-styrylxanthines as A 2selective antagonists, however, this gap has been largely filled now (Shimada et al, 1992;Jacobson et al, 1993; for some examples of structures see also Fig.…”