Increased inhibitory action against adenosine 5′‐triphosphate in the isolated taenia of the guinea‐pig caecum by substitution in the A‐ring of 2‐phenylisatogen

Abstract

1 The ability of a series of 17 isatogen derivatives to relax smooth muscle, inhibit adenosine 5'-diphosphate (ADP)-stimulated respiration in isolated mitochondria and to antagonize the inhibitory effects of adenosine 5'-triphosphate (ATP) on smooth muscle was measured. 2 Substitution in the 4-and 7-positions of the A-ring gave compounds that were strong inhibitors of mitochondrial ATP synthesis and potent, non-specific smooth muscle relaxants. The compounds also possessed ATP-receptor blocking activity. 3 Substitution in the 5-and 6-positions of the A-ring decreased both the relaxant effect on smooth muscle and inhibition of ATP synthesis, whilst enhancing ATP-receptor antagonism. 4 In a series of 6-substituted 2-phenylisatogens, 6-methoxy-2-phenylisatogen was the most effective ATP-receptor antagonist. This compound also showed the greatest separation of the desired, pharmacological activity (ATP-receptor blockade) from the other two activities (smooth muscle relaxation and inhibition of mitochondrial ATP synthesis).

Purine and Pyrimidine (P2) Receptors as Drug Targets

“…Pyridylisatogen tosylate, 67 (PIT), is a weak P2 receptor antagonist that also displayed strong receptor-independent vasorelaxant effects . At cloned P2Y 1 receptors, PIT acts as an allosteric enhancer of agonist action …”

“…287 At cloned P2Y 1 receptors, PIT acts as an allosteric enhancer of agonist action. 288 NBD chloride, 69 (Figure 7), selectively blocked ADPinduced aggregation of platelets through covalent modification of aggregin, a putative (non-P2) ADP receptor, on the cell surface. 289 The potent activity of the ω-conotoxin GVIA 142 suggests that other snail-derived peptides may function as P2X antagonists, in line with their broad effects on other ion channels.…”

Interactions between Antimalarial Indolone-N-oxide Derivatives and Human Serum Albumin

“…These compounds possess interesting biological properties. Some isatogens show in vitro antibacterial and antifungal activities, elicit smooth muscle relaxation , and have neuroprotective effects, and some 2-arylisatogens have antitubercular and hypertensive properties. As part of our search for new lead compounds for the treatment of malaria, we recently showed that indolone- N -oxide derivatives (INODs) have antiplasmodial activities .…”

Pharmacological properties of indolone-N-oxides controlled by a bioreductive transformation in red blood cells?

“…In mammalian systems they inhibit the synthesis of adenosine triphosphate (ATP) in mitochondria. 1 In vitro, indolone-N-oxides show antibacterial 2,3 and antifungal activities, 4 elicit smooth muscle relaxation, 5,6 and are neuroprotective. 7 These compounds, containing nitrone functional group, are capable of trapping hydroxyl and superoxide radicals.…”