Quaternary-Lipophilic Carbamates with Blood Brain Barrier Permeability as Potential Drugs for the Treatment of Diseases Associated with Cholinergic Deficiency

Abstract

Cholinergic deficiency in the central nervous system may be associated with cognitive impairment (1–3). In pathological conditions such as Alzheimer’s disease (AD) cholinergic deficiency has been described in discrete brain regions such as the nucleus basalis of Minert, cerebral cortex and the hippocampus (4, 5). 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 tested as potential treatment for AD, while tacrine (THA, Cognex) and E2020 (Aricept) have already been approved by the FDA for AD treatment. PHY displayed mild positive benefits (6), yet, its short half-life and relatively high acute toxicity limit its clinical use. THA is 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 major disadvantages (7, 8). 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 (9). PYR is also used for pretreatment against poisoning by organophosphorus insecticides and nerve agents (6). However, its quaternary positively charged pyridinium nitrogen limits its permeability into the CNS and confines its use only as a peripheral cholinomimetic drug. Early efforts to develop tertiary analogues of PYR failed since they displayed lower efficacy than PYR as AChE inhibitors (10). New PYR derivatives that cross the blood-brain barrier (BBB), have longer duration of action, and less toxic than other AChE inhibitors may provide a new series of choli-nomimetics with improved efficacy and safety.