piperidines and amiridine

This is a review of the data available in the literature and the authors' own findings on pathogenetical rationale for the use and clinical study of current treatments for Alzheimer's disease (AD) (synonym: Alzheimer-type dementia). In the past decade many attempts have been made at targeting different links of the pathogenesis of a neurodegenerative process that underlie AD. Several areas of pathogenetical therapy for AD have been developed on the basis of experimental studies and pilot clinical tests. The most developed areas are as follows: various compensatory (replacement) treatments aimed at overcoming neurotransmitter deficit in different neuronal systems that are damaged in AD to a greater or lesser extent; neuroprotective therapy promoting increased viability (survival) of neurons and their plasticity, and vasoactive therapy. Rather new directions of AD pathogenetic therapy, such as antiinflammatory and hormonal therapy along with antiamyloid therapeutic strategies are still under study.

Topics: Aged; Alzheimer Disease; Amino Acids; Aminoquinolines; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Donepezil; Dopamine Agents; Estrogens; Ginkgo biloba; Humans; Indans; Memantine; Monoamine Oxidase Inhibitors; Multicenter Studies as Topic; Neuronal Plasticity; Neuroprotective Agents; Neurotransmitter Agents; Nicergoline; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Piracetam; Pyrithioxin; Rivastigmine; Selegiline; Tacrine; Time Factors

This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Animals; Benzazepines; Brain; Butyrylcholinesterase; Carbamates; Cholinesterase Inhibitors; Donepezil; In Vitro Techniques; Indans; Inhibitory Concentration 50; Male; Phenylcarbamates; Physostigmine; Piperidines; Rats; Rivastigmine; Tacrine; Time Factors

The effects of NIK-247 on cholinesterase, scopolamine-induced amnesia and spontaneous movement were examined and compared with those of the well-known cholinesterase inhibitors tacrine and E-2020. NIK-247, tacrine and E-2020 all strongly inhibited acetylcholinesterase (AChE) in human red blood cells (IC50s = 1.0 x 10(-6), 2.9 x 10(-7) and 3.7 x 10(-8) M, respectively). In addition, NIK-247 and tacrine, but not E-2020, strongly inhibited butyrylcholinestrase (BuChE) in human serum. All three drugs produced mixed inhibition of AChE activity. Moreover, the inhibitory effect of NIK-247 on AChE was reversible. All compounds at 0.1-1 mg/kg p.o. significantly improved the amnesia induced by scopolamine (0.5 mg/kg s.c.) in rats performing a passive avoidance task. The three compounds at 1 and 3 mg/kg p.o. did not significantly decrease spontaneous movement by rats. These findings suggest that NIK-247 at a low dose (0.1-1 mg/kg p.o.) improves scopolamine-induced amnesia but does not affect spontaneous movement. The findings suggest that NIK-247 may be a useful drug for the treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Amnesia; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Male; Motor Activity; Piperidines; Psychotropic Drugs; Rats; Rats, Wistar; Scopolamine; Tacrine