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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. 

    • 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:

  • Inactivation of acetylcholine by the enzyme acetylcholinesterase

     

• 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.

  • Acetylcholinesterase Active Site

• 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.