Document Detail


Synthesis and structure-activity relationships for biphenyl H3 receptor antagonists with moderate anti-cholinesterase activity.
MedLine Citation:
PMID:  18976927     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-10-17
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  16     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-17     Completed Date:  2009-01-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  9911-24     Citation Subset:  IM    
Affiliation:
Dipartimento Farmaceutico, Università degli Studi di Parma, V. le G.P. Usberti 27/A, I-43100 Parma, Italy.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biphenyl Compounds / chemical synthesis,  chemistry*,  pharmacology*
Cells, Cultured
Cholinesterase Inhibitors / chemistry*,  pharmacology*
Guinea Pigs
Histamine Antagonists / chemical synthesis,  chemistry*,  pharmacology*
Humans
Piperidines / chemical synthesis,  chemistry,  pharmacology
Rats
Receptors, Histamine H3 / drug effects*
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/(1-(2-(4'-piperidinomethyl-biphenyl-4-yl)ethyl)piperidine); 0/Biphenyl Compounds; 0/Cholinesterase Inhibitors; 0/Histamine Antagonists; 0/Piperidines; 0/Receptors, Histamine H3

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