Dual-acting drugs: an in vitro study of nonimidazole histamine H3 receptor antagonists combining anticholinesterase activity
| Autor: | Mara Comini, Vigilio Ballabeni, Lisa Flammini, Massimo Coruzzi, Francesca Saccani, Elisabetta Barocelli, Simona Bertoni, Matteo Incerti, Giovanni Morini |
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| Rok vydání: | 2010 |
| Předmět: |
Guinea Pigs
Pharmacology Inhibitory postsynaptic potential Biochemistry Structure-Activity Relationship Piperidines In vivo Drug Discovery medicine Animals Humans Receptors Histamine H3 General Pharmacology Toxicology and Pharmaceutics Receptor Cholinesterase biology Chemistry Organic Chemistry Rats Tacrine biology.protein Molecular Medicine Cholinergic Cholinesterase Inhibitors Histamine H3 receptor Antagonism medicine.drug Histamine H3 Antagonists |
| Zdroj: | ChemMedChem. 5(7) |
| ISSN: | 1860-7187 |
| Popis: | 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 multi-factorial 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. |
| Databáze: | OpenAIRE |
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