| Popis: |
Cholinergic deficiency in the central nervous system is associated with cognitive impairment (Bartus et al, 1982, Fisher and Heldman, 1990, Wilson and Cook, 1994). In pathological conditions such as Alzheimer’s disease (AD) cholinergic deficiency has been consistently observed in discrete brain regions such as the nucleus basalis of Meynert, cerebral cortex and the hippocampus (Sims, 1983; Tegliavini, 1984). Therefore, a rational approach for the treatment of such cognitive impairments would be to elevate the level of acetylcholine in brain. Cholinesterase (ChE) inhibitors such as the carbamates physostigmine (PHY) and ENA-713 have been clinically examined as potential treatments for AD, while tacrine (THA, Cognex) and E2020 (Aricept) have already been approved by the FDA for AD treatment. PHY displayed mild positive benefits (Millard and Broomfield, 1995), yet, its short half-life and relatively high acute toxicity could limit its clinical use. THA is indeed a long-acting reversible ChE inhibitor but its hepatotoxicity and peripheral side effects on the gastrointestinal system such as nausea and vomiting combined with its moderate efficacy only at high doses constitute its major disadvantages (O’Brien et al, 1991; Crimson, 1994). Pyridostigmine (PYR) is a reversible ChE inhibitor that is less toxic than PHY and has a longer duration of action than PHY. PYR serves as an effective drug for the treatment of myasthenia gravis (Pascuzzi, 1994). PYR is also used for the pre-treatment against poisoning by organophosphorus insecticides and nerve agents (Millard, 1995). However, its quaternary positively charged pyridinium nitrogen limits its permeability into the CNS and confines its use only as a peripheral cholinomimetic drug. Earlier efforts were made to develop tertiary analogues of PYR but they displayed lower efficacy than PYR as AChE inhibitors (Arnal, 1990). The development of PYR derivatives that could cross the blood-brain barrier (BBB), will have longer duration of action and will also be less toxic than other AChE inhibitors that are currently evaluated for AD treatment, will provide a new series of cholinomimetics with improved efficacy and safety. |
