Current Drug Discovery Technologies, 2008, 5, 000-000 1 1570-1638/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Advances in Drug Discovery to Assess Cholinergic Neurotransmission: A Systematic Review Vitor F. Ferreira* ,1 , David R. da Rocha 1 , Kátia G. Lima Araújo 2 and Wilson C. Santos 3 1 Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Outeiro de S. João Batista s/n Centro 24020-150, Niterói, RJ, Brazil 2 Departamento de Bromatologia, Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mário Viana 523, Santa Rosa 24241-000, Niterói, RJ, Brazil 3 Departamento de Farmácia e Administração Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mário Viana 523, Santa Rosa 24241-000, Niterói, RJ, Brazil Abstract: Neurotransmission is essential to physiological processes of cellular communication. The search for new molecules that may influence neurotransmission systems is an open field with possible impact on several pathophysiological conditions or diseases: Alz- heimer’s disease, Parkinsonism and myasthenia gravis, etc. The present review describes the most important aspects of cholinergic neu- rotransmission, as well as natural and synthetic compounds that, as clinical or experimental drugs, are able to influence this transmission. The pharmacological effects of substances that bind to muscarinic or nicotinic cholinergic receptors, along with their corresponding af- finities will also be presented. Key Words: Cholinergic neurotransmission, cholinergic receptors, carbohydrates. INTRODUCTION Since the beginnings of mankind, much effort has been devoted to comprehending human bodily functions. At the beggining, the search for information about ourselves was basically driven by curi- osity. However, over the centuries, sanitary, social and economical aspects have become the concerns driving research. Nevertheless, and despite the great advances, understanding of how the nervous system works is still a challenge. For example, the morphophysiopathological changes in cholinergic neurotransmission, an essential physiological event that controls a variety of human func- tions and may determine many disorders and diseases, still need to be better understood. Continued efforts to study the mechanisms control- ling these biological functions and to speed up the development of new drugs with high degree of specificity and fewer side effects are necessary. New drugs are needed to treat some still not understood diseases. Thus, Parkinson’s [1] disease, Alzheimer’s [2] disease, mus- cular dystrophies, motor neuron diseases and myasthenia gravis [3], are all disorders in which new therapeutic approaches are urgently needed. Nowadays the pharmacologic approaches to these diseases are mostly palliative and it is not easy to prevent their progression. Drugs that will improve quality of life as well as reduce their serious impact on public health will always be desirable. In this review we wish to present an overview of the currently understood biochemical aspects of cholinergic neurotransmission and different synthetic and natural molecules with a view to considering their usefulness in some diseases involving cholinergic neurotrans- mission. NEUROTRANSMISSION Neurotransmission is the process whereby nervous system cells communicate among themselves and with others cells of the organ- ism through nerve impulses. This process produces responses in smooth, cardiac and skeletal muscles and glands [4]. This fundamen- tal physiological event is mediated by some specific chemical com- pounds called neurotransmitters. Many of them are involved in di- verse body functions: they include noradrenaline, dopamine and *Address correspondence to this author at the Departamento de Química Orgânica, Insti- tuto de Química, Universidade Federal Fluminense, Outeiro de S. João Batista s/n Centro 24020-150, Niterói, RJ, Brazil; E-mail: cegvito@vm.uff.br histamine [4]. Acetylcholine (ACh, 1, Fig. (1)), the first neurotrans- mitter to be identified, acts in the central and peripheral cholinergic nerves of many organisms [5] and is involved in many functions, including excitability [6], attention [7, 8], learning [9], memory [10, 11] and stress response [12]. Fig. (1). Acetylcholine (1) chemical structure. Acetylcholine (1) is biosynthesized in specific neurons by choline acetyltransferase, which uses choline and acetyl coenzyme A as pre- cursors. The resulting neurotransmitter is stored in synaptic vesicles, from where it is released to the synaptic cleft by depolarization in a process called exocytosis [4]. The enzyme acetylcholinesterase (AChE) converts acetylcholine into the inactive metabolites choline and acetate [13, 14]. AChE is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essen- tial for proper muscle function [4]. Once released, the neurotransmit- ter (1) acts as the physiologic ligand on the pre- and post-synaptic receptor sites [15] (Fig. (2)). In the synaptic cleft, acetylcholine binds to two kinds of choliner- gic receptors: a) muscarinic receptors (M), which belong to the me- tabotropic receptor family; and b) nicotinic receptors (N), which be- long to the ionotropic receptor family [16]. This nomenclature origi- nated in the observation that acetylcholine mimicked the pharmacol- ogical effects of the natural alkaloids, muscarine ( 2) and nicotine (3), that were employed to discover the receptors (Fig. ( 3)). NICOTINIC RECEPTORS Nicotinic acetylcholine receptors (nAChRs) are proteins with a molecular weight of about 280 kDa that are found in the central and peripheral nervous system [17]. These receptors are made up of five subunits ( , , , or ) that combine to form homologous or identical pentamers, and are arranged so as to form a central ionic channel [18- 21] (Fig. (4)). The nAChRs muscle form is located at the final portion of the neuromuscular junction, and has five subunits: two subunits, one subunit, one subunit and either a or a subunit, while the neuronal forms are much more heterogeneous, presenting a wide Me O O N Me Me Me Cl Acetylcholine (1)