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

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• 作者：Catia Lambertucci ; Mayya Sundukova ; Dhuldeo D. Kachare ; Deepak S. Panm ; Diego Dal Ben ; Michela Buccioni ; Gabriella Marucci ; Anna Marchenkova ; Ajiroghene Thomas ; Andrea Nistri ; Gloria Cristalli ; Rosaria Volpini
• 关键词：Purinergic receptors ; P2X3 receptor ; P2X3 receptor antagonists ; Adenine derivatives ; Purine derivatives ; ATP ; Purine ; Patch clamp
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：65
• 期：Complete
• 页码：41-50
• 全文大小：1177 K

文摘

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 ¦Á,¦Â-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)-N⁶-methyl-9H-purine-2,6-diamine (24), which appears to be a good antagonist on recombinant and native P2X3 receptors with IC₅₀?=?1.74?¡À?0.21?¦ÌM.