East meets west in the search for Alzheimer's therapeutics - Novel dimeric inhibitors from tacrine and huperzine A

W. M. Li, K. K W Kan, P. R. Carlier, Yuan-Ping Pang, Y. F. Han

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is linked to cholinergic deficiency and the overactivation of glutamate receptors. The acetylcholinesterase (AChE) inhibition treatment approach has produced the most encouraging results in clinical practice, and memantine, a moderate antagonist of N-methyl-D-aspartate (NMDA) receptors, has been approved for treating AD. However, AChE inhibitors have limited success as they only improve memory in mild dementia but cannot stop the process of neurodegeneration; while memantine possesses neuroprotective effects only with a little ability in memory enhancement. There has been a major rush among neuroscience research institutions and pharmaceutical firms worldwide to search for safer and more effective therapeutic agents for AD. The novel dimers, derived from tacrine and the fragment of huperzine A (HA'), have been demonstrated to be potent and selective reversible inhibitors of AChE. Bis(7)-tacrine, bis(12)-hupyridone (E12E) and HA'(10)-tacrine, are representatives of three series of novel dimers. According to the preclinical studies, these compounds have been shown to have low toxicity and high efficacy for improving cognitive deficits in several animal models. More interestingly, bis(7)-tacrine, similar to memantine, prevents glutamate-induced neurotoxicity by moderately blocking glutamate receptor NMDA subtype. Furthermore, bis(7)-tacrine, as well as E12E, possesses multiple neuroprotective effects in vitro and in vivo. Taking together, these dimeric AChE inhibitors, especially bis(7)-tacrine, E12E and HA'(10)-tacrine, may provide beneficial effects in AD and other neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)386-396
Number of pages11
JournalCurrent Alzheimer Research
Volume4
Issue number4
DOIs
StatePublished - Sep 2007

Fingerprint

Tacrine
Memantine
Cholinesterase Inhibitors
Alzheimer Disease
Glutamate Receptors
Neuroprotective Agents
Aptitude
N-Methylaspartate
Therapeutics
Acetylcholinesterase
Neurosciences
N-Methyl-D-Aspartate Receptors
Neurodegenerative Diseases
Cholinergic Agents
Dementia
Glutamic Acid
Animal Models
1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine
huperzine A

Keywords

  • Acetylcholinesterase inhibitor
  • Alzheimer's disease
  • Bis(7)-tacrine
  • Dimers
  • Neuroprotection

ASJC Scopus subject areas

  • Biological Psychiatry
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health

Cite this

East meets west in the search for Alzheimer's therapeutics - Novel dimeric inhibitors from tacrine and huperzine A. / Li, W. M.; Kan, K. K W; Carlier, P. R.; Pang, Yuan-Ping; Han, Y. F.

In: Current Alzheimer Research, Vol. 4, No. 4, 09.2007, p. 386-396.

Research output: Contribution to journalArticle

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