General principles

Spr21_1 S 2021 Bb Lecture Introduction to Pharm



Chemical aspects of drugs

Drug shape

  • The shape of the drug is an important factor in defining the nature of the drug-receptor interaction.

    • The three-dimensional shape of the drug is thought to interact with a complementary structural binding region of the receptor, typically a protein.

      • The specific nature of the interaction defines whether the drug acts as an agonist promoting a change in cellular function or as an antagonist which blocks the receptor usually resulting in no direct biological effect.

    • For example, let's consider acetylcholine or a synthetic analogue bethanechol (Urecholine).

      • Interaction of these molecules with receptor (nicotinic or muscarinic cholinergic receptor) causes a physiological response -- a decrease in heartbreak for instance.

        • By contrast, a muscarinic antagonist such as atropine may bind even more tightly than acetylcholine to muscarinic receptor but causes no direct effect.

          • However, following administration of antagonist a biological response may be observed as a result of receptor blockade.

      • A clinical example would be bradycardia following acute myocardial infarction.

        • Bradycardia in this context might be due to excessive parasympathetic (cholinergic) tone and might cause unacceptably low cardiac output or predispose tomore serious arrhythmias.

        • Administration of atropine, by blocking the muscarinic receptor blunts the action of acetylcholine and accordingly may reverse bradycardia.

  • Now let's consider the specific example,acetylcholine, as the 2D planar structure:





  • On the left side of the molecule note the quaternary (always positively charged) Nitrogen, which is part of the choline component of acetylcholine.





  • The synthesis of acetylcholine proceeds by combination of choline and acetate (as Acetyl-CoA)-see below




  • Now let's examine the 3-D structure of choline.

    • By convention, nitrogen atoms are blue, oxygen red and carbon gray.



  • Similarly we can examine interactively the 3-D structure of acetylcholine:


    • Note above the presence of an "ester" linkage [O in red] between the choline moiety and the seal group.

    • This ester bond is susceptible to hydrolysis, i.e. breakage which may be catalyzed by esterases (acetylcholinesterase is an example).

    • Acetycholine:

    • 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

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).

The biological action acetylcholine is terminated by hydrolysis, catalyzed by the enzyme acetylcholinesterase.

    • The overall reaction is shown here:

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






  • Acetylcholinesterase


  • The image above 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 to interact 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.