title: 2',3'-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents.
abstract: Blocking membrane currents evoked by the activation of purinergic P2X3 receptors localized on nociceptive neurons represents a promising strategy for the development of agents useful for the treatment of chronic pain conditions. Among compounds endowed with such antagonistic action, 2',3'-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) is an ATP analogue, whose inhibitory activity on P2X receptors has been previously reported. Based on the results of molecular modelling studies performed with homology models of the P2X3 receptor, novel adenosine nucleotide analogues bearing cycloalkyl or arylalkyl substituents replacing the trinitrophenyl moiety of TNP-ATP were designed and synthesized. These new compounds were functionally evaluated on native P2X3 receptors from mouse trigeminal ganglion (TG) sensory neurons using patch clamp recordings under voltage clamp configuration. Our data show that some of these molecules are potent (nanomolar range) and reversible inhibitors of P2X3 receptors, without any apparent effect on trigeminal GABAAand 5-HT3receptors, whose membrane currents were unaffected by the tested compounds.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.affiliation: Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Marchenkova
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy.
authors.forename: Ajiroghene
authors.initials: A
authors.lastname: Thomas
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Spinaci
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.affiliation: Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, (MC), Italy. rosaria.volpini@unicam.it.
authors.forename: Rosaria
authors.identifier: 0000-0002-5304-5232
authors.initials: R
authors.lastname: Volpini
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D051379:Mice; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects*
chemical_list: D000700:Analgesics; D058920:Purinergic P2X Receptor Antagonists; D058477:Receptors, Purinergic P2X3; C045674:2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate; D000255:Adenosine Triphosphate
keywords: ATP derivatives; Molecular modelling; P2X3 receptor antagonists; Patch clamp; Purine derivatives; Purinergic receptors