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Kierunki poszukiwania nowych leków wpływających na procesy uczenia i zapamiętywania, poprawiających rozpoznawanie

Malawska B.

Wiadomości Chemiczne

2001

[Z] 55, 1-2

67-92

This review attempts to briefly summarise the recent developments in the study of new compounds improving learning, memory and cognitive function. A large number of compounds belonging to many different chemical classes have been proposed as cognition enhancers. Three groups of compounds - nootropics, cholinergic drugs and neuromodulators are presented . Most compounds described as nootrpics are 2-pyrrolidone derivatives, the prototype of which is piracetam (Nootropil) . Nootropics facilitate learning and memory in animal models. Clinical trials have yielded unconvincing results, however some new drugs such as nefiracetam and fasoracetam appear promising. Central cholinergic systems have been repeatedly shown to play an important role in learning and memory. The deficits in cognitive and memory performance observed in aged humans and in Alzheimer's disease (AD) patients are due at least in part to deficient cholinergic functioning. Augmentation of cholinergic neurotransmission might be accomplished in several different ways. Cholinergic agonists directly acting on muscarinic receptors may improve the defective cholinergic function seen in AD. Selective second-generation muscarinic agonists appear promising and are in various stages of preclinical and clinical evaluation, including milameline, itameline, xanomeline, sabcomeline and talsaclidine. These compounds are chemically related to the naturally occurring muscarinic agonist, arecoline. The prototypical neuronal acetylcholine receptors agonist nicotine has been shown to ameliorate some of the symptoms of AD, and, in a number of animal models, to have neuroprotective effects. Some nicotinic agonists were reported to be active in animal models of memory and learning, such as compounds ABT-418, ABT-089 and SIB-1553A . Acetylcholinesterase (AChE) inhibition is presently the most successful method to ameliorate cholinergic deficit and lead to symptomatic improvement. About 30 AChE inhibitors are currently being studied word-wide in preclinical or clinical studies. AChE inhibitors are broadly classified in three categories. These include: the carbamates such as physostigmine, eptastigmine, phenserine and rivastigmine; the aminoacridines such as tacrine, velnacrine, suronacrine, and their derivatives ipidacrine and compound SM-10888 ; the benzylpiperidines such as donepezil, T-82, TAK-147 and CP-118954. Tacrine was the the first drug approved in 1993 in USA for treatment of senile dementia of the Alzheimer type. Rivastigmine, and donepezil were approved in 1997. Cymserine and bis-norcimserine are derivatives of the alkaloid physostigmine. These compounds represent the first available potent, reversible, and selective inhibitors of butyrylcholinesterase. The organophosphate metrifonate has been extensively studied in animals and recently evaluated in AD. Metrifonat is an inactive prodrug, but is non-enzymatically transformed into the active compound dichlorvos that irreversibly inhibits AChE. There are many reports on the interaction between the cholinergic system and other putative neurotransmitter on the central nervous system. Therefore, such transmitter interactions play an important role in the regulation of learning and memory. Modulators, the third group of compounds represents different structures. A wide variety of substances have been shown to facilitate memory, including: opioid agonist (SA 4503), a benzodiazepine inverse agonist (S-8510), modulator of noradrenergic transmission (CR 2249) ; derivatives of piperazine (FK-960, ensaculine) and peptides (NC-1900) .