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• Acetycholine:

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    • Although acetylcholine is depicted as a "static" molecule in terms of internal rotation,, acetylcholine and many other drugs exhibit free rotation around internal bonds.

    • For acetylcholine,tau₁, tau₂, tau₃, represent torsion angles and refer to the degree of twist around these bonds of free rotation

    • Specific additional analysis is required to determine which three-dimensional form of acetylcholine appears to be preferred for binding to the cholinergic receptor.  The configuration of acetylcholine and solution is quite different than the configuration when bound to the nicotinic cholinergic receptor (using two-dimensional NMR to estimate  bond angles)

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    • Above figures adapted from Principles of Drug Action: The Basis of Pharmacology, Third Edition, edited by William . B. Pratt and Palmer Taylor, Churchill Livingston, New York, 1990. pp 20-23. Above Acetylcholine conformation figure -- original work: Behling, RW, Yamane T, Gavon G, Jelinski LW: Conformation of Acetylcholine Bound to the Nicotinic Acetylcholine Receptor. Proc Natl Acad Sci USA 85:6721, 1988.

  • Some short-acting pharmacological agents are in fact short-acting because they are rapidly hydrolyzed at an ester linkage.

    • Ester-type local anesthetics

    • Esmolol (Brevibloc)

    • Remifentanil (Ultiva).

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• The biological action acetylcholine is terminated by hydrolysis, catalyzed by the enzyme acetylcholinesterase: The overall reaction  is shown below --

• Acetylcholinesterase itself is a large, complex protein which has its primary catalytic function the extremely rapid hydrolysis of the neurotransmitter acetylcholine.

Acetylcholinesterase

• The image below illustrates the relationship between the very small molecule, acetylcholine, and its specific interaction within the very large molecule, acetylcholinesterase.

• This image illustrates how the neurotransmitter acetylcholine represented above the in ball-and-stick form is recognized by specific amino acids within acetylcholinesterase's active site.

  •  The positive charge of acetylcholine (due to the permanently positive quaternary nitrogen) interacts with tryptophan-84 (Trp-84) and phenylalanine-330 (Phe-330), through cationic (+ charged)- π-electron interactions}

  • This part of the acetylcholinesterase molecule is referred to as the "aromatic gorge"

  • The negatively charged amino acid, glutamatic acid-199 (Glu-199) is thought also contract with acetylcholine through ionic-type interactions

  • This image was created by Dr. Ricky Cox in the Department of Chemistry, Murray State University as part of research into the role of Noncovalent Interactions in ligand-protein interactions. Image used with permission.