title: Synthesis and structure-activity relationships for biphenyl H3 receptor antagonists with moderate anti-cholinesterase activity.
abstract: The combination of antagonism at histamine H(3) 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 H(3)-antagonists. Starting from these premises, the current work presents an expanded series of histamine H(3) 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 H(3) 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 pIC(50)=5.96 for cholinesterase inhibition and high H(3) 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 H(3)-antagonists with anti-cholinesterase activity.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, V. le G.P. Usberti 27/A, I-43100 Parma, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Morini
authors.forename: Mara
authors.initials: M
authors.lastname: Comini
authors.forename: Mirko
authors.initials: M
authors.lastname: Rivara
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bordi
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Plazzi
authors.forename: Lisa
authors.initials: L
authors.lastname: Flammini
authors.forename: Francesca
authors.initials: F
authors.lastname: Saccani
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.forename: Vigilio
authors.initials: V
authors.lastname: Ballabeni
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C534074:(1-(2-(4'-piperidinomethyl-biphenyl-4-yl)ethyl)piperidine); D001713:Biphenyl Compounds; D002800:Cholinesterase Inhibitors; D006633:Histamine Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3