Characterization of "mini-nucleotides" as P2X receptor agonists in rat cardiomyocyte cultures. An integrated synthetic, biochemical, and theoretical study
B. Fischer et al., Characterization of "mini-nucleotides" as P2X receptor agonists in rat cardiomyocyte cultures. An integrated synthetic, biochemical, and theoretical study, J MED CHEM, 42(14), 1999, pp. 2685-2696
The design and synthesis of "mini-nucleotides", based on a xanthine-alkyl p
hosphate scaffold, are described. The physiological effects of the new comp
ounds were evaluated in rat cardiac cell culture regarding Ca2+ elevation a
nd contractility. The results indicate biochemical and physiological profil
es similar to those of ATP, although at, higher concentrations. The biologi
cal target molecules of these "mini-nucleotides" were identified by using s
elective P2-R and A(1)-R antagonists and P2-R subtype selective agonists. O
n the basis of these results and of experiments in Ca2+ free medium, in whi
ch [Ca2+](i) elevation was not observed, we concluded that interaction of t
he analogues is likely with P2X receptor subtypes, which causes Ca2+ influx
. Theoretical calculations analyzing electronic effects within the series o
f xanthine-alkyl phosphates were performed on reduced models at quantum mec
hanical levels. Calculated dipole moment vectors, electrostatic potential m
aps, and volume parameters suggest an explanation for the activity or inact
ivity of the synthesized derivatives and predict a putative binding site en
vironment for the active agonists. Xanthine-alkyl phosphate analogues prove
d to be selective agents for activation of PBX-R subtypes, whereas ATP acti
vated all P2-R subtypes in cardiac cells. Therefore, these analogues may se
rve as prototypes of selective drugs aiming at cardiac disorders mediated t
hrough P2X receptors.