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Dual‐Acting Drugs: an in vitro Study of Nonimidazole Histamine H 3 Receptor Antagonists Combining Anticholinesterase Activity
Author(s) -
Incerti Matteo,
Flammini Lisa,
Saccani Francesca,
Morini Giovanni,
Comini Mara,
Coruzzi Massimo,
Barocelli Elisabetta,
Ballabeni Vigilio,
Bertoni Simona
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000008
Subject(s) - pharmacology , in vitro , histamine , chemistry , dual (grammatical number) , histamine h3 receptor , histamine receptor , receptor , medicine , antagonist , biochemistry , art , literature
Dual‐acting compounds that combine H 3 antagonism with anticholinesterase properties are currently emerging as a novel and promising therapeutic approach in the treatment of multifactorial disorders primarily characterized by cholinergic deficits such as Alzheimer's disease. A series of novel nonimidazole H 3 ligands was developed from the chemical manipulation of 1,1′‐octa‐, ‐nona‐, and ‐decamethylene‐bis‐piperidines—H 3 antagonists that had been the subject of previous investigations. These compounds were evaluated for in vitro binding affinity, antagonistic potency, and selectivity at rodent and human histamine H 3 receptors, inhibitory activity at rat brain cholinesterase, and in vivo CNS access and cholinomimetic effects. Within the present series, the tetrahydroaminoacridine hybrid 18 stands out as one of the most attractive molecules, synergistically combining nanomolar and selective H 3 antagonism with remarkable anticholinesterase activity. From this original starting point, it is hoped that future investigations will lead to dual‐acting compounds that can selectively enhance central cholinergic neurotransmission and thus facilitate the treatment of cognitive disorders.