The objective of the proposed research is to delineate the modes of interaction of a particular class of drugs with the nicotinic cholinergic receptor and to elucidate the mechanism by which these drugs activate the ion channel of the receptor to cause cation transport. The drugs to be used are physostigmine, neostigmine and pyridostigmine, which are routinely utilized in the treatment of the human disease Myasthenia Gravis, because of their well known ability to inhibit cholinesterase. These drugs have also been found to be acetylcholine receptor activators that are not inhibited by classical cholinergic antagonists. Because of the chronic nature of Myasthenia Gravis, myasthenic patients are treated with these drugs for many years: their unexpected ability to activate the acetylcholine receptor, and the unusual pharmacological properties of their activating action, may explain the frequent hypersensitivity to these drugs which develop in myasthenic patients. Elucidation of the molecular mechanisms of the dual action of these drugs on the esterase and the acetylcholine receptor, two essential components of neuromuscular transmission, is therefore important for their proper clinical use. At the molecular level, it is of considerable importance to determine whether a neurotransmitter receptor can be activated by a pathway(s) different by that triggered by the native transmitter. The drug action will be studied at the biophysical and biochemical level using spectroscopic approaches, such as fluorescence and nuclear magnetic resonance spectroscopy, and also by chemical labelling approaches, in order to delineate binding and activation mechanisms and to determine the structural domains of the acetylcholine receptor involved in interaction with these drugs.
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