Med Chem Lecture 18

Front 1

The thyroid gland is highly ____? What kind of strucute? Where is it located? It is composed of what? How are they joined?

Back 1

The thyroid gland is a highly vascular, flat structure located at the upper portion of the trachea, just below the larynx. It is composed of two lateral lobes joined by an isthmus across the ventral surface of the trachea.

Front 2

The Thyorid gland is the source of two fundamentally different types of hormones which are what? What are both hormones vital for?

Back 2

thyroxine(T4) and triiodothyronine(T3). Both hormones are vital for normal growth and development and control essential functions, such as energy metabolism and protein synthesis.

Front 3

Baumann, who discovered that the thyroid gland was the only organ in mammals that had the capability to incorporate what? What was the discovery important for?

Back 3

to incorporate iodine into organic substances. That discovery was important in research concerning the phylogeny of the thyroid.

Front 4

Major clues to the physiological roles of thyroid hormones were provided when normal and abnormal thyroid function were related to what 2 things?

Back 4

related to oxygen uptake and when thyroid hormones were found to induce metamorphosis in tadpoles.

Front 5

A patient lacking thyroid hormones may be treated with ____ or ___?

Back 5

synthetic hormones or natural preparations

Front 6

The development of synthetic thyroid hormones has significantly improved treatment of hypothyroidism by decreasing what?

Back 6

the variations in thyroxine (T4) and triiodothyronine (T3) blood levels that often resulted from inconsistent bovine and porcine sources.

Front 7

Thyroid hormones are what kind of functional groups? Derived from what? They are synthesized where and stored where?

Back 7

Thyroid hormones are iodinated amino acids derived from L-tyrosine. They are synthesized in the thyroid gland and stored as amino acid residues of thyroglobulin.

Front 8

The first known biologically active iodine-containing compound of the thyroid gland was isolated from thyroid extracts and named what?

Back 8

L-thyroxine (T4).

Front 9

Twenty-five years later, with the availability of chromatographic techniques and radioactive iodine, researchers discovered another major thyroid hormone, which was identified as what?

Back 9

3,5,3’-triiodo-L-thyronine (T3).

Front 10

How is T3 compared to T4? What is it synthesized by?

Back 10

This far more potent hormone is largely synthesized from T4 by deiodinase enzymes outside the thyroid.

Front 11

T3 and T4 influence what 5 components?

Back 11

These thyroid hormones influence carbohydrate metabolism, protein synthesis and breakdown, and cardiovascular, renal, and brain function.

Front 12

The thyroid gland also contains two quantitatively important iodinated amino acids which are what?

Back 12

diiodo-L-tyrosine (DIT) and monoiodo-L-tyrosine (MIT).

Front 13

In addition, there are small amounts of other iodothyronines, such as what 2?

Back 13

3,3’-diiodo-L-thyronine (T2) and 3,3’,5’-triiodo-L-thyronine (reverse T3 [rT3]).

Front 14

Thyroid hormones are produced by what? Why?

Back 14

Thyroid hormones are produced by the follicular cells of the thyroid gland. Because the effects of T4 in vivo are mediated via T3 (T4 is converted to T3 in target tissues) T3 is 3- to 5- fold more active than T4).

Front 15

Thyroglobulin is of special importance, because it serves as the matrix for what?

Back 15

for the synthesis of T4 and T3 and as the storage form of the hormones and iodide.

Front 16

What are 5 Iodinated compounds of the Thyroid gland?

Back 16

Front 17

Thyroperoxidase(TPO) is the enzyme responsible for what?

Back 17

for aromatic iodination of tyrosine residues in thyoglobulin(TG).

Front 18

Noniodinated TG is secreted through what? Iodide enters the follicular cell by what? Then Transported where?

Back 18

through the apical membrane of the follicular cell into the follicular lumen.

by the iodide pump (NIS, sodium iodide symporter) and is then transported into the follicular lumen.

Front 19

In the lumen, the iodide is oxidized by what? What does this form? Followed by aromatic what? What constitutes the major products? What also is produced?

Back 19

by the oxidized/activated form of TPO to form hypoiodate anion (OI-), followed by aromatic iodination of selected tyrosyl residues on TG to form diiodotyrosyl (DIT) and monoiodotyrosyl (MIT) residues. Diiodotyrosyl residues constitute the major products, but some MIT peptides also are produced.

The tyrosyl ring

Front 20

The tyrosyl ring of DIT couples with adjacent DIT and MIT residues with an ether linkage to form the outer ring of what? What donor site does this leave?

Back 20

T4 and T3,both of which remain attached to TG, leaving dehydroalanine at the donor site.

Front 21

Natural Thyroid Hormone Preparations what 2 components?

Back 21

Natural preparations include desiccated thyroid and thyroglobulin.

Front 22

Desiccated thyroid and thyroglobulin (partially purified) are derived from what? What are these hormone released by?

Back 22

derived from thyroid glands of domesticated animals that are used for food by human.
are released by the proteolytic activity of our intestinal tract.

Front 23

Are desiccate preparations compared to synthetic hormones?

Back 23

Desiccated preparations are less expensive than synthetic hormones but have been shown to produce variable T4/T3 blood levels because of inconsistencies both between and within animal sources of the thyroid gland.

Front 24

Synthetic, crystalline thyroid hormones are more what? What do they contain? What 4 drugs are of present interest?

Back 24

Of present interest are T4 (levothyroxine), T3 (liothyronine), dT4 (dextrothyroxine), and T4-T3 mixtures (Liotrix).

Front 25

With levothyroxine, firmer binding to carrier proteins causes a slower what? Compared to what?

Back 25

With levothyroxine, firmer binding to carrier proteins causes a slower onset of action than crystalline T3 or a desiccated thyroid preparation.

Front 26

Liothyronine sodium (Cytomel) has a rapid what? Short what? IT is the therapy of choice for what?

Back 26

Liothyronine sodium (Cytomel) has a rapid onset and short duration of action. It is the therapy of choice when it is desirable to have rapid onset or cessation of activity.

Front 27

Conformational Properties of Thyroid Hormones and Analogues

What is important for biological activity? What kind of orientation is favored? Why is it favored?

Back 27

The diphenyl ether conformation is important for biological activity. A perpendicular orientation of the planes of the aromatic rings of 3,5-diiodothyronines would be favored to minimize interactions between the bulky 3,5-iodines and the 2’,6’-hydrogens.

Front 28

Conformational Properties of Thyroid Hormones and Analogues

In this orientation, the 3’- and 5’-positions of the ring are not conformationally equivalent, and the 3’-iodine of T3 could be oriented either which way?

Back 28

distal (away from) or 5’ proximal (closer) to the side chain–bearing ring.

Front 29

The structures of representative distal analogues I and II and of the proximal analogues III and IV were synthesized and the results of an assay for T4 activity clearly indicates what>

Back 29

clearly indicates that in 2’-blocked analogues, a distal 3’-substitution is favorable for thyromimetic activity, but a proximal 5’-substitution is not.