The Role of Aromatic Substitution on Dihydropyridine Binding, Page 1

The Role of Aromatic Substitution on 1,4-Dihydropyridine Binding

OBJECTIVES

To view the active conformation of the 1,4-dihydropyridine class of calcium channel blockers.
To illustrate the steric (and hence activity) difference for this series of compounds.

INTRODUCTION
The 1,4-dihydropyridines (DHPs), exemplified by desnitro-nifedipine, are one of three chemical classes of calcium channel blockers. These compounds have been shown to be very effective vasodilators and are useful in the treatment of hypertension, ischemic heart disease, and other cardiovascular disorders. Desnitro-nifepine is not commercially available, but is used here due to its simplicity. Commercially available compounds are all related to the general structure shown on the right. The major sites of variation among the currently available DHPs are the ester side chains (R1 and R2) of the 1,4-dihydropyridine ring and the substituents (X) on the aromatic ring. Variation of the esters has been reported to alter the potency, duration of action, onset of action and other pharmacokinetic properties, while the substitution on the aromatic ring is thought to be important in locking the compound in its active conformation. This exercise will demonstrate the influence that aromatic substitution can have on the conformation, and hence the activity, of a dihydropyridine. Please note that desnitro-nifedipine has been numbered to correspond to the model shown below and does not follow any chemical standard. In contrast, the general structure has been numbered according to proper chemical nomenclature.

Part 1: Observation of the Active Conformation of the 1,4-DHPs
Shown on the right is a 3-D model of the active conformation of the DHPs. Use the structure of desnitro-nifedipine shown above to orient yourself to this 3-D structure. Note that in this active conformation, the aromatic ring lies in such a manner that it bisects and is perpendicular to the dihydropyridine ring. In this orientation, H[34], an ortho hydrogen, lies directly above the midpoint of the 1,4-DHP ring. Any structural feature that acts to restrict free rotation about the C[23]-C[24] bond will "lock in" the active conformation and will enhance activity. To date, this conformational restriction has been provided by substitutions on the aromatic ring. Structures of all currently available 1,4-DHPs are provided in your lecture notes. You should note that all of these structures contain aromatic substitutions at either the ortho and/or meta positions.

The main purpose of this part of the exercise is for you to observe this active conformation from a variety of different vantage points. Specifically, there are two views in addition to the "default" overhead view which are very useful. Please follow the directions in order.

Back View: Select the “Rotate” control. Place your mouse cursor in the center of the bottom of the structure screen. CLICK AND HOLD your mouse button, and move it in a straight line towards the top of structure. The structure will rotate along the y-axis. Try to rotate the structure approximately 90 degrees (this does not need to be exact). Please note: If you make an error, you can always reload/refresh the page and try again! Using this view:

Find H[32], H[31], and H[41], the para, meta, and ortho hydrogens, respectively. Hint: If you start at the top of the molecule, you will sequentially encounter these atoms. (Note: H[25] is part of the 1,4-DHP ring and will not be used in this exercise).
Change to "Space Filling" view by clicking on the “down arrow” of the “Display” control. Again identify the para, meta, and ortho hydrogens (it is usually easier to find them in this mode.

Side View: Select the “Rotate” control again, and place your mouse cursor in the center of either the right or left side the structure screen. As before, CLICK AND HOLD your mouse button and move it in a straight line to the opposite side (i.e., either to the left or right, depending upon where you started). It does not matter which direction you rotate the molecule (either direction will provide the side view).

Find C[24], the carbon on the aromatic ring which is directly attached to the 1,4-DHP ring. You will need to be able to locate this on the next page to answer question 1.

Additional Views: Randomly rotate the molecule (using both the "Space Filling" and "Ball and Stick" views until you feel that you have a good appreciation of the shape of this active conformation.

Navigation
Intro / Question 1 / Question 2 / Questions 3&4

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This site was developed and is maintained by Dr. Marc W. Harrold (harrold@duq.edu)
Copyright, September 2001; Revised, 9/18/07.