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

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 (pKi = 8.70; pKB = 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.

A series of H3-antagonists with a 4,4′-biphenyl scaffold was developed, in which the terminal groups were modulated, providing compounds with high H3 receptor binding affinity and antagonist potency, together with moderate anti-cholinesterase activity.Figure optionsDownload as PowerPoint slide