Analogues of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) as potential anti-platelet-aggregation agents.

Abstract

Dense granules of platelets contain a high content of diadenosine 5',5r-Pl,P4-tetraphosphate (Ap4A). We

A peptide isolated from a random phage peptide library is a structural mimic to the P1, P4‐diadenosine 5′‐tetraphosphate binding site on its receptor

“…This Ap 4 A-induced calcium mobilization modulates catecholamine secretion in chromaffin cells [14] and activates pro-tein kinase C [15]. These data are consistent with extracellular Ap 4 A altering diverse physiological processes through the activation of second messenger systems.…”

“…Ap 3A, Ap4A, Ap5A, and Ap6A are stored at high concentrations in dense secretory granules of platelets and are released into the blood following stress [1Ϫ5]. Our laboratory has demonstrated the presence of membrane receptors for Ap 4 A in brain, liver, kidney, cardiac, spleen, and adipose tissue [6]. The presence of the receptor in a diversity of tissue type supports the notion that circulating Ap 4 A is a modulator of cellular functions.…”

“…Our laboratory has demonstrated the presence of membrane receptors for Ap 4 A in brain, liver, kidney, cardiac, spleen, and adipose tissue [6]. The presence of the receptor in a diversity of tissue type supports the notion that circulating Ap 4 A is a modulator of cellular functions. Indeed extracellular Ap 4 A has been shown to modulate blood vessel tone [7,8], inhibit platelet aggregation [4], prime respiratory burst, regulate apoptosis in neutrophils [9], induce catecholamine release from chromaffin cells [3], activate glycogen phosphorylase in hepatocytes [10], and elicit contraction in vas deferens [11] and urinary bladder [12,13].…”

“…The presence of Ap 4 A receptors has been demonstrated on cardiac myocytes [16], on chromaffin cells [17], on brain synaptosomes [18], and on hepatocytes [19]. However, the nature of the receptor involved in Ap 4 A-mediated cellular signaling is unclear.…”

“…There is evidence that binding of extracellular Ap 4 A initiates intracellular calcium mobilization. This Ap 4 A-induced calcium mobilization modulates catecholamine secretion in chromaffin cells [14] and activates pro-tein kinase C [15].…”