title: Evaluation of adenine as scaffold for the development of novel P2X3 receptor antagonists.
abstract: Ligands that selectively block P2X3 receptors localized on nociceptive sensory fibres may be useful for the treatment of chronic pain conditions including neuropathic pain, migraine, and inflammatory pain. With the aim at exploring the suitability of adenine moiety as a scaffold for the development of antagonists of this receptor, a series of 9-benzyl-2-aminoadenine derivatives were designed and synthesized. These new compounds were functionally evaluated at rat or human P2X3 receptors expressed in human embryonic kidney (HEK) cells and on native P2X3 receptors from mouse trigeminal ganglion sensory neurons using patch clamp recording under voltage clamp configuration. The new molecules behaved as P2X3 antagonists, as they rapidly and reversibly inhibited (IC50 in the low micromolar range) the membrane currents induced via P2X3 receptor activation by the full agonist α,β-methyleneATP. Introduction of a small lipophilic methyl substituent at the 6-amino group enhanced the activity, in comparison to the corresponding unsubstituted derivative, resulting in the 9-(5-iodo-2-isopropyl-4-methoxybenzyl)-N(6)-methyl-9H-purine-2,6-diamine (24), which appears to be a good antagonist on recombinant and native P2X3 receptors with IC50 = 1.74 ± 0.21 μM.
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.forename: Mayya
authors.initials: M
authors.lastname: Sundukova
authors.forename: Dhuldeo D
authors.initials: DD
authors.lastname: Kachare
authors.forename: Deepak S
authors.initials: DS
authors.lastname: Panmand
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Anna
authors.initials: A
authors.lastname: Marchenkova
authors.forename: Ajiroghene
authors.initials: A
authors.lastname: Thomas
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristalli
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058477:Receptors, Purinergic P2X3; D011994:Recombinant Proteins; D000225:Adenine
keywords: 2′,3′-O-(2,4,6-trinitrophenyl)-ATP; ATP; Adenine derivatives; CPU; DCM; DRG; HTS; Hill coefficient; MOE; Molecular Operating Environment; NOE; P2X3 receptor; P2X3 receptor antagonists; PPADS; PPP; PTLC; PTSA; Patch clamp; Purine; Purine derivatives; Purinergic receptors; TBAN; TEA; TFAA; TG; TLC; TNP-ATP; central processing unit; dichloromethane; dorsal root ganglion; high-throughput screening; n(H); nuclear Overhauser effect; p-toluenesulfonic acid; preparative thin-layer chromatography; pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid; rise time; tetrabutylammonium nitrate; thin-layer chromatography; time constant of desensitization decay; triethylamine; trifluoroacetic anhydride; trigeminal ganglia; triphosphate; α,β-meATP; α,β-methyleneATP; τ(des1;2); τ(on)