2-(N'-alkylidenehydrazino)adenosines: Potent and selective coronary vasodilators

Article abstract of DOI:10.1021/jm00102a007

The reaction of aliphatic aldehydes and ketones with 2-hydrazinoadenosine under relatively mild conditions (at room temperature or in refluxing methanol) formed 2-(N'-alkylidenehydrazino)-adenosines, 5-22, in good yields. Two kinds of adenosine receptors regulate cardiac and coronary physiology. In supraventricular tissues an A₁AR coupled to muscarinic K channels mediates the negative chronotropic, dromotropic, and inotropic actions of adenosine, and an inhibitory A₁AR coupled to adenylate cyclase mediates the 'antiadrenergic' action of adenosine. One or more kinds of A₂ receptors mediate coronary vasodilation. Bioassays employing a guinea pig heart Langendorff preparation showed that 5-22 weakly retard impulse conduction through the AV node (negative dromotropic effect), but several analogues were very active coronary vasodilators. The coronary vasoactivity of the (n- alkylidene- and of the (isoalkylidenehydrazino)adenosines paralleled the length of the alkyl chain, the EC₅₀s of the most active n-pentylidene (8) and isopentylidene (18) congeners being 1 nM. The EC₅₀s of the cyclohexylmethylene (9), cyclohexylethylidene (10), and cyclohex-3- enylmethylene (12), analogues were likewise <1 nM, but the cyclohex-1- enylmethylene congener 12 was 10 times less active than 9. The unselective adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (0.1 mM) raised the EC₅₀s of the negative dromotropic effects of 8, 9, and 18 by 5-28-fold and the EC₅₀s of coronary vasodilation of 22-90-fold. Catalytic reduction of 9 increased the hydrophobicity and changed the UV spectrum, suggesting reduction of the -CH=N- bond. The product darkened on exposure to air and so was not characterized further. A new method for preparing 2',3',5'-tri-O- acetyl-2,6-dichloropurine riboside, a precursor in the synthesis of 2- hydrazinoadenosine, consists of the addition of tert-butyl nitrite to a mixture of 2',3',5'-tri-O-acetyl-6-chloroguanosine and CuCl in CHCl₃ saturated with Cl₂.