Stereochemistry Considerations

A detailed Summary of Stereochemistry Considerations

What would you think if I gave you a drug and said this is going to help you but I want you to know ahead of time that 50% of the dose is not affected, in fact the drug is 50% not pure. The idea of that would make you feel you want another drug. The reality of that is that a large # of drugs we give are 50% impure and the reason is b/c so many drugs we give are racemic mixtures, a 50:50 mixture of enantiomers. Most drugs that demonstrate optical activity only one isomer is pharmalogically active, so what that means is that we are giving a product where 50% of it is inactive. There are some important considerations you have to take into account when you have drugs that are optically active and what we would like to do today is take the things we have gone thru this semester where we have really ignored stereochemistry thru that whole process and talk about the times in which you need to consider aspects of stereochemistry. This has become a big issue now the FDA has pushed for drug companies to be able to characterize both isomers when giving a racemic mixture, also to force manufactures to only market the active isomer and not going with the standard practice of giving a drug which is

R-(-)- is levorotatory but with absolute configuration R

So now interaction with the receptor is significantly different because of this slight geometric change. That's why geometry is important because in order to exert its effect most drugs have to interact with a macromolecule and so the geometry of the drug becomes very important in that interaction and a slight change may move from a 3 point interaction to a 2 point interaction which can have a big impact on the effect you exert. It may take a drug from being pharmalogically active to being inactive, an example of that can be seen with Ketamine.

Remember when you talk about stereochemistry you are talking about a carbon atom which has 4 different ligands. In this case when you have four different ligands this is asymmetric and often referred to as a chiral carbon. This results in 2 mirror images that can not be superimposed. On pg.152 what is shown is an example of L(+) alanine and D(-) alanine and no matter how many times you try to twist and turn that molecule you can never superimpose the left hand side on top of the right hand side. You cannot superimpose optically active isomers, you recall from organic chemistry that when you have this type of situation that such a compound will rotate plane polarized light and one isomer will rotate in one direction and the other isomer in the other. A compound that rotates it to the right is dextrorotatory and that is signified using the term d or (+). A substance that turns it to the left is levoratatory and is signified as L or (-). You also remember when you have a pair of nonsuperimposable images like this there are different words used to describe them. Sometimes they are called optical isomers, optical antipodes, most commonly in the drug literature they are referred to as enantiomers. What is extremely important to recognize is that enantiomers are chemically identical., they have the same melting point, kp, same solubility, same lipophilicity. From a chemical point of view they are identical the only difference is there geometric configuration, that is the only place they are not identical. The other thing you will recognize is that the rotation of plane polarized light does not indicate the configuration. The absolute configuration is generally determined by X-ray crystallography and you recall that the designations for this based on the actual geometric configurations is

What is shown on pg.133 is two enantiomers which have a significant different pharmacologic effect in terms of taste. This is d-carvone (caraway) and on the right is l-carvone (spearmint), The only difference here is the geometric configuration. Now how can you have compounds that are mirror images of one another and yet have such different taste? It relates to their ability to interact with receptors. For example if we have a chiral carbon and we have our 4 substituents and it interacts with the receptor designated here as 3 points on the receptor designated as B' C' D' and these are the points of interaction on the molecule. If now we look at the mirror image of that compound and try to rearrange this, we can never rearrange it in a way where we get more than 2 sites of interaction . We are only going to be able to combine 2 sites at once.

Some common words found in the essay are:
C' D', Nomenclature Remember, Stereochemistry Considerations, S-IBU R-IBU, Louis Pasteur, Significance Stereoisomers, RS SR, S-IBU CoA, R-/S- R---, plane polarized, optically active, polarized light, plane polarized light, racemic mixtures, isomer potent, geometric configuration, organic chemistry, absolute configuration, racemic mixture, pure enantiomer, activity rr isomer, rotation plane polarized, difference activity isomers, rr isomer potent, RR SS,

Approximate Word count = 4674
Approximate Pages = 19 (250 words per page double spaced)

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