Synthesis and direct C2 functionalization of imidazolium and 1,2,4-triazolium N-imides.

Pd-catalyzed direct C2 arylation and Cu-catalyzed direct one-pot alkynylation/intramolecular cyclization of azolium N-imides are reported. Various acetylenes, aryl iodides, and 1-alkyl substituents were examined. The mild protocol allows direct C2 arylation of azolium N-imides without the use of specialized reagents together with novel one-pot regioselective preparations of imidazole-pyrazolo and pyrazolo-1,2,4-triazole ring systems. The electronic properties of selected examples were examined by fluorescence spectroscopy.

Evaluation of adenine as scaffold for the development of novel P2X3 receptor antagonists.

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,ß-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.