Antagonists and the purinergic nerve hypothesis: 2,2′-pyridylisatogen tosylate (PIT), an allosteric modulator of P2Y receptors. A retrospective on a quarter century of progress

Abstract

2,2′-Pyridylisatogen tosylate (PIT) is a selective antagonist of P2Y responses in smooth muscle and does not antagonise the effects of adenosine. Responses to purinergic nerve stimulation are resistant to PIT. PIT is an allosteric modulator of responses to ATP in recombinant P2Y₁ receptors expressed in Xenopus oocytes with potentiation of ATP at low concentrations (0.1–10 μM) and antagonism at higher ones (>10 μM). A radioligand binding profile showed that PIT did not interact with any other receptors, with the exception of low affinity for the adenosine A₁ receptor (pK_i, 5.3). The compound recognises purine sites and then may cause irreversible binding to sulfhydryl groups following prolonged incubation or high concentrations. PIT is a potent spin trapper.