A number of pharmaceutically important organic compounds have a structure with exactly two chiral centers. An organic molecule with two chiral centers can exist as four stereoisomers which are usually, but not always, distinct. A classic example of a set of molecules with two chiral centers is the tetrose sugars, shown below in Fischer projections; the Fischer projection is a convenient way to illustrate the concepts of enantiomer and diastereomer (Fischer projections can be rotated in the plane of the paper but not taken out of the plane); the R/S designation is from the CIP system; lower case d = dextrorotatory (+) or clockwise rotation of polarized light; lower case l = levorotatory (-) or counterclockwise rotation of polarized light; uppercase D & L refer to structure designations developed by Emil Fischer based on the configuration of glyceraldehyde (see original sources for more info; the D sugar is the one with an R configuration at the methylene furthest from the carbonyl). Note that D is not the same as d, and l is not the same as L. While for the tetrose sugars both D enantiomers are l (-), this is not a general trend. D-Glucose is d (+), and there is not a general tendency for the D or L enantiomers to be d (+) or l (-).
A molecule with two chiral centers forms a set of four stereoisomers composed of two distinct diastereomers with each diastereomer composed of two distinct enantiomers. The enantiomers are identical except for the fact that they are non-superimposable mirror images. The diastereomers are different molecules with different physical properties. The one situation wherein enantiomers behave differently is in a chiral (left handed or right handed) environment, such as exists in all living things. There is a degenerate case for a molecule with two chiral centers when a mirror plane can be drawn through the molecule. As is always the case, a molecule with a mirror plane is achiral.
Recognition of the existence of a meso compound is straightforward with Fischer projections. When a molecule with two chiral centers has an identical top half and lower half, then the (R,S) & (S,R) pair will be a single meso compound while the (R,R) & (S,S) pair will be enantiomers. See the example of tartaric acid above. Note that (d/l) tartaric acid enantiomers can't be superimposed while the mirror image of meso tartaric acid is superimposable on the original.
In most cases, only one of the four possible stereoisomers are active as a given type of pharmaceutical agent, or, at least, one stereoisomer is significantly more active than the others. A classic example of a set of pharmaceutical compounds derived from a molecule with exactly two chiral centers is the lysergic acid diethylamide (LSD) group. Only (+)-(5R,8R)-LSD is a psychoactive psychedelic hallucinogen. See below for the structures of the four stereoisomers of LSD along with a brief summary of one synthetic strategy for producing LSD.
Recalling basic pharmacology, many psychoactive drugs act by taking the place of an endogenous neurotransmitter at the active site of an important brain cell membrane receptor protein. If the pharmaceutical agent fits the active site perfectly in its deactivated state, then the agent will likely act as an antagonist. If the pharmaceutical agent fits the active site perfectly in its activated state, then the agent will likely be an agonist. The action of LSD is not well understood, but it is known that LSD acts as both an agonist and antagonist at various serotonin and dopamine receptors throughout the human brain and body. Given that the active site of a neurotransmitter receptor protein has a very specific and chiral shape, it is understandable why only one of the four possible stereoisomers is active.
Another interesting example of a set of psychoactive molecules composed from the four stereoisomers of an organic molecule with two chiral centers is the ephedrine/pseudoephedrine group. See the structure of these four molecules below. All four molecules have unique stimulant/medicinal activity.
Note that the receptor can also be an enzyme active site. Consider the case of the erectile dysfunction (ED) agent Tadalafil. The most common sort of ED drug is the PDE5 (phosphodiesterase type 5) inhibitor of which Tadalafil is an example. The PDE5 inhibitors are antagonists of the normal action of the PDE5 enzyme. The PDE enzymes convert the smooth muscle dilating agent cGMP (cyclic guanosine monophosphate) into an inactive hydrolyzed form. By preventing the breakdown of cGMP, PDE5 inhibitors amplify and sustain whatever erectile response is left in the individual taking the drug. The active site of a PDE5 enzyme has, like all enzymes and neurosensory protein receptors, a very specific active site. So, it is not surprising that one stereoisomer in the Tadalafil group is active. See the four stereoisomers in the tadalafil family below:
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