Synthesis and structure–activity relationships for biphenyl H₃ receptor antagonists with moderate anti-cholinesterase activity

详细信息    查看全文

• 作者：Giovanni Morini ; Mara Comini ; Mirko Rivara ; Silvia Rivara ; Fabrizio Bordi ; Pier Vincenzo Plazzi ; Lisa Flammini ; Francesca Saccani ; Simona Bertoni ; Vigilio Ballabeni ; Elisabetta Barocelli ; Marco Mor
• 关键词：Histamine H₃ receptor ; H₃-antagonist ; Cholinesterase inhibition ; Structure– ; activity relationship
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：1 December 2008
• 年：2008
• 卷：16
• 期：23
• 页码：9911-9924
• 全文大小：441 K

文摘

The combination of antagonism at histamine H₃ receptors and inhibition of acetylcholinesterase has been recently proposed as an approach to devise putative new therapeutic agents for cognitive diseases. The 4,4′-biphenyl fragment has been reported by us as a rigid scaffold leading to potent and selective non-imidazole H₃-antagonists. Starting from these premises, the current work presents an expanded series of histamine H₃ receptor antagonists, characterized by a central 4,4′-biphenyl scaffold, where the structure–activity profile of both mono-basic and di-basic compounds is further explored and their ability to inhibit rat brain cholinesterase activity is determined. The steric properties and basicity of the terminal groups were modulated in symmetrical compounds, carrying identical substituents, and in asymmetrical compounds, having a piperidine ring at one end and different groups at the other. The length of the linker connecting the biphenyl scaffold to the terminal groups was also modulated. Binding studies at rat and human H₃ receptors evidenced the highest binding affinities for di-basic compounds, in the order of nM concentrations, and that the steric requirements for the two terminal groups are different. Many potent compounds showed good selectivity profiles over the other histamine receptors. Interestingly, some derivatives displayed a moderate ability to inhibit rat brain cholinesterase, for example compound 12 (1-[2-(4′-piperidinomethyl-biphenyl-4-yl)ethyl]piperidine) has a pIC₅₀ = 5.96 for cholinesterase inhibition and high H₃ receptor binding affinity and antagonist potency (pK_i = 8.70; pK_B = 9.28). These compounds can be considered as rigid analogs of a recently reported class of dual-acting compounds and as a promising starting point for the design of new H₃-antagonists with anti-cholinesterase activity.