Cholinergic drugs are presently the first line of symptomatic treatment of Alzheimer's dementia. The classical approach to cholinergic therapy in AD is inhibition of the enzyme acetylcholinesterase (AChE) that breaks down the neurotransmitter acetylcholine (ACh) thereby destroying the signal of cholinergic neurotransmission. There are at least two drawbacks associated with this therapeutic approach,
Activation and inactivation cycles of nicotinic receptors
In cholinergic therapy of AD, nAChR desensitization must be avoided, as it is detrimental to the intended cholinergic enhancement. Consequently, the potency of AChE inhibitors to be used in therapy is limited to levels that are capable of producing sufficient cholinergic enhancement, however do not yet induce significant desensitization of nAChR. Such conditions are difficult to adjust by drugs that act as so called “covalent AChE inhibitors”, e.g. carbamates and organophosphates, such as rivastigmin and metrifonate. In these cases, the esters formed between the acids of the inhibitors and the active serine residue of the enzyme dissociate only slowly, thereby delaying liberation of the enzyme. Thus, reversible rather than covalent AChE inhibitors are recommended as drugs for AD treatment.
To maintain the physiologically required balance between transiently elevated ACh levels for nAChR activation and rapid inactivation of ACh after each excitatory event, the local expression levels of nAChR and AChE are tightly controlled by a feedback mechanism. If ACh levels do not rapidly drop to basal levels between excitatory events, the AChE expression is up-regulated. Consequently, chronically applied AChE inhibitors always induce some up-regulation of AChE expression.
With these considerations in mind, the pros and cons of available drug classes
can be summarized as follows:
GalantosPharmahas used several approaches to develop new nicotinic APL.Setting
out from galantamine as a clinically proven natural compound, three properties
We have aimed to developing four types of improved APL:
In the following, we shall focus on the latter approach, and in particular on the so called pro-drug approach.