Title:Medicinal Chemistry of P2X Receptors: Agonists and Orthosteric Antagonists
Volume: 22
Issue: 7
Author(s): Catia Lambertucci, Diego Dal Ben, Michela Buccioni, Gabriella Marucci, Ajiroghene Thomas and Rosaria Volpini
Affiliation:
Keywords:
P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, P2X7, P2X receptor agonists, P2X receptor antagonists.
Abstract: In this work, we have highlighted data reported in the literature trying to draw a complete picture
of the structures and biological activity of agonists and orthosteric antagonists of P2X receptors. Actually,
only few P2X receptor agonists have been found and most of them are derived from modification of the
natural ligand ATP and they are P2X receptor subtype unselective. In particular, BzATP (9) is one of the
most potent P2X receptor agonists with EC50 value in the nanomolar range at some subtypes. Differently
from agonists, P2X receptor antagonists belong to different chemical classes such as high molecular weight aryl polysulfonate
molecules like suramin and its simplified derivatives and anthraquinone compounds. All these molecules proved to
be non selective at P2X receptors, and they are endowed with micromolar activity and not favourable pharmacokinetic
properties due to the presence of several charged groups. Also modification of the natural ligand ATP led to the discovery
of P2X receptor antagonists like TNP-ATP (29), which, although not selective, showed high potency at P2X1, P2X3 (IC50
of 0.006 µM and 0.001 µM, respectively), and heteromeric P2X2/3 receptors. Also the dinucleotide inosine polyphosphate
Ip5I (33) was found to be a potent and selective antagonist at P2X1 vs P2X3 receptors with IC50 = 0.003 µM. A significant
improvement has been gained from the interest of pharmaceutical companies that in the last years discovered, through the
use of high-throughput screening, potent and selective antagonists endowed with novel structures, some of which are currently
in clinical trials for several therapeutic applications.
