Adenine-based acyclic nucleotides as novel P2X3 receptor ligands.
A new series of acyclic nucleotides based on the adenine skeleton and bearing in 9-position a phosphorylated four carbon chain has been synthesized. Various substituents were introduced in 2-position of the adenine core. The new compounds were evaluated on rat P2X3 receptors, using patch clamp recording from HEK transfected cells and the full P2X3 agonist alpha,beta-meATP as reference compound. The results suggest that certain acyclic nucleotides, in particular compounds 28 and 29, are endowed with modest partial agonism on P2X3 receptors. This is an interesting property that can depress the function of P2X3 receptors, whose activation is believed to be involved in a number of chronic pain conditions including neuropathic pain and migraine. In fact, the new acyclic nucleotides are able to persistently block (by desensitization) P2X3 receptor activity after a brief, modest activation, yet leaving the ability of sensory neurons to mediate responses to standard painful stimuli via a lower level of signaling.
Volpini
Rosaria
R
Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Mishra
Ram Chandra
RC
Kachare
Dhuldeo D
DD
Dal Ben
Diego
D
Lambertucci
Catia
C
Antonini
Ippolito
I
Vittori
Sauro
S
Marucci
Gabriella
G
Sokolova
Elena
E
Nistri
Andrea
A
Cristalli
Gloria
G
D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D058477:Receptors, Purinergic P2X3; D013329:Structure-Activity Relationship
D000227:Adenine Nucleotides; D008024:Ligands; C546407:P2RX3 protein, human; C546410:P2rx3 protein, rat; D058910:Purinergic P2 Receptor Agonists; D058477:Receptors, Purinergic P2X3