Tacrine characterized

Patani GA, Pang YP, Chien YW (2005) A potent and selective tacrine analog-biomembrane permeation and physicochemical characterization. Pharm Dev Tech-nol 10 525-538. 

The devastating mental deterioration that characterizes Alzheimer s disease has been attributed to a mishandling of the neurotransmitter acetylchohne. Inhibitors of acetylcholinesterase, the enzyme that catabolizes that substance, would be expected to help restore deficient acetylcholine levels. Several partly reduced acridines have shown some activity in treating Alzheimer s disease. At least one of these, tacrine (14-5), is now approved for use in patients. The initial step in the synthesis of the first of these consists of the sodium amide catalyzed condensation of isatin (14-1) with cyclohexanone. The reaction can be visualized by assuming the first step to involve an attack of amide on isatin to give an amido-amide such as (14-2) (note that no attempt has been made to account for charges). This can then react with... 

Overdosage with cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, and seizures. Increasing muscle weakness may occur and can result in death if respiratory muscles are involved. Tertiary anticholinergics, such as atropine, may be used as an antidote for tacrine overdosage. 

K. Runze, and W.F. Trager (1993). Characterization of tacrine metabolism and bioactivation using heterologous expression systems and inhibition studies Evidence for CYP1A2 involvement. In Abstracts, 5th North American ISSX Meeting, Vol. 4, p. 139, 17-21 October, Tucson, AZ. 

Acetylcholine Approximately 5% of brain neurons have receptors for ACh. Most CNS responses to ACh are mediated by a large family of G protein-coupled muscarinic M receptors that lead to slow excitation when activated. The ionic mechanism of slow excitation involves a decrease in membrane permeability to potassium. Of the nicotinic receptors present in the CNS (they are less common than muscarinic receptors), those on the Renshaw cells activated by motor axon collaterals in the spinal cord are the best-characterized. Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors used in Alzheimer s disease (eg, tacrine) and the muscarinic blocking agents used in parkinsonism (eg, benztropine). 

Stachlewitz RF, Arteel GE, Raleigh JA, Connor HD, Mason RP, Thurman RG (1997) Development and characterization of a new model of tacrine-induced hepatotoxicity role of the sympathetic nervous system and hypoxia-reoxygenation. J Pharmacol Exp Ther... 

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