Structure Activity Relationships of Thyroid Hormones:  The Role of the Iodine Atoms

OBJECTIVES

  1. To view the active conformation of the thyroid hormones
  2. To illustrate the importance of the 3- and 5-iodo groups in determining thyroid activity.
  3. To illustrate the importance of the 3'- and 5'-iodo groups and to use this information to explain why T3 is more active than T4.
INTRODUCTION
Liothyronine (T3) and levothyroxine (T4) represent the biologically active thyroid hormones.  They are synthesized in the body by coupling reactions of monoiodotyrosine (MIT) and diiodotyrosine (DIT).  Other structurally similar compounds, such as reverse T3 and 3,3'-diodothyronine (T2) are inactive as thyroid hormones, and represent metabolites of T3 and T4.

In evaluating the structures above, it should be noted that all four compounds contain an L-alanine side chain, two aromatic rings linked by an ether bridge, and a phenolic hydroxyl group.  All of these structural features have been shown to be essential and will not be discussed further.  The only structural difference among these compounds is the number and position of the iodine atoms.  These iodine atoms are extremely important for activity and determine the structure-activity relationships for this set of compounds.  Please note the numbering system for the two aromatic rings.  Ring A, the one directly connected to the L-alanine group, uses the designations 1-6 for ring substitution, while ring B, the one containing the phenol hydroxyl group, uses the designations 1'-6'.   The iodines are located at positions 3, 5, 3' and 5'.  By convention, if only one iodine atom is present in a ring, the ring is numbered so as to designate the iodine atom as either a 3- or 3'-iodo, regardless of how it is drawn!  In this exercise, Chem3D models will be used to observe the active conformation of the thyroid hormones and to examine the roles that the various iodine atoms have in determining activity.

There are three facts that can be explained by evaluating the number and position of the iodine atoms:

  1. T3 is more active than T4.
  2. T2 and rT3 are inactive.
  3. T4 has a longer duration of action than T3
This exercise will focus on explanations for the first two facts only.  An explanation of the duration (item #3) does not require molecular modeling and will be discussed in lecture.

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This site was developed and is maintained by Dr. Marc W. Harrold (harrold@duq.edu)
Copyright, August 2001.