Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease

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• 作者：Pedro Gonz谩lez-Naranjo ; Natalia P茅rez-Macias ; Nuria E. Campillo ; Concepci贸n P茅rez ; Vicente J. Ar谩n ; Rocio Gir贸n ; Eva S谩nchez-Robles ; Mar铆a Isabel Mart铆n ; Mar铆a G贸mez-Ca帽as ; Mois茅s Garc铆a-Arencibia ; Javier Fern谩ndez-Ruiz ; Juan A. P谩ez
• 关键词：Alzheimer's disease ; Antioxidant ; BuChE inhibitor ; CB2R agonist ; Drug design ; Indazole ether ; Multitarget drug
• 刊名：European Journal of Medicinal Chemistry
• 出版年：12 February, 2014
• 年：2014
• 卷：73
• 期：Complete
• 页码：56-72
• 全文大小：1482 K

文摘

Designing drugs with a specific multi-target profile is a promising approach against multifactorial illnesses as Alzheimer's disease. In this work, new indazole ethers that possess dual activity as both cannabinoid agonists CB2 and inhibitors of BuChE have been designed by computational methods. On the basis of this knowledge, the synthesis, pharmacological evaluation and docking studies of a new class of indazoles has been performed. Pharmacological evaluation includes radioligand binding assays with [³H]-CP55940 for CB1R and CB2R and functional activity for cannabinoid receptors on isolated tissue. Additionally, in聽vitro inhibitory assays of AChE/BuChE and the corresponding competition studies have been carried out. The results of pharmacological tests have revealed that three of these derivatives behave as CB2 cannabinoid agonists and simultaneously show BuChE inhibition. In particular, compounds 3 and 24 have emerged as promising candidates as novel cannabinoids that inhibit BuChE by a non-competitive or mixed mechanism, respectively. On the other hand, both molecules show antioxidant properties.