科研之友
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摘要
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 H-3 octa, nona, and decamethylene bis piperidines-H-3 antagonists that had been the subject of previous invesstigations. 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 hybride 18 stands out as one of the most attractive moleculesynergistically 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.
- 出版日期2010-7-10
