New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties

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• 作者：Rafael Leó ; n ; Cristó ; bal de los Rí ; os ; José ; Marco-Contelles ; Oscar Huertas ; Xavier Barril ; F. Javier Luque ; Manuela G. Ló ; pez ; Antonio G. Garcí ; a ; Mercedes Villarroya
• 关键词：Tacrine-dihydropyridine hybrids ; AChE ; BuChE ; Kinetic analysis ; Inhibition mechanism ; Voltage-dependent calcium channels ; Neuroprotection ; Molecular modeling
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：15 August 2008
• 年：2008
• 卷：16
• 期：16
• 页码：7759-7769
• 全文大小：1288 K

文摘

In this communication, we describe the synthesis and biological evaluation of tacripyrimedones 1–5, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzo[b,g][1,8]naphthyridine-1(2H)-one. These multifunctional compounds are moderately potent and selective AChEIs, with no activity toward BuChE. Kinetic analysis and molecular modeling studies point out that the new compounds preferentially bind the peripheral anionic site of AChE. In addition, compounds 1–5 show an excellent neuroprotective profile, and a moderate blocking effect of L-type voltage-dependent calcium channels due to the mitigation of [Ca²⁺] elevation elicited by K⁺ depolarization. Therefore, they represent a new family of molecules with potential therapeutic application for the treatment of Alzheimer’s disease.