Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
Drugs and the places in the body they bind to are each three-dimensional molecular structures. As a result, the interaction between a drug and a binding site, such as on a metabolic enzyme, a reuptake transporter, or a neurotransmitter receptor, is a three-dimensional event. How tightly this binding occurs (high versus low affinity) and the functional activity that results from this interaction (i.e., whether the drug is an agonist or antagonist) in part depends on the “fit” between the three-dimensional configuration of the drug and the binding site. Changes in the three-dimensional structural configuration of a drug may therefore influence its binding and activity at a particular site. In this article, I describe the main principles of chirality and stereochemistry, which are essential for understanding psychopharmacology in 3-D. In particular, thinking about and understanding this information will lay the groundwork for next month’s article, in which I review examples of drug therapies where chirality and stereochemistry are clinically relevant.
Stereoisomers, Chirality, and Enantiomers
Isomers are compounds with the same chemical formula (having the same number and type of atoms) but different structures (the atoms are arranged differently within their molecular structure). This difference in arrangement can yield profound differences in the biochemical properties demonstrated by each isomer. Stereoisomers are compounds that possess the same molecular and structural formula but differ in the orientation of their individual atoms in space. When referring to a chemical compound, the term chirality (derived from the Greek word chiros, meaning “handed”) is based on this different spatial configuration of atoms. Chirality implies a particular form of stereoisomerism that occurs when a carbon atom has four different chemical groups (substituents) attached to it. The substituent group may be a single atom (e.g., a hydrogen atom) or a functional group of atoms (e.g., a methyl or ethyl group). The manner in which the four substituent groups are arranged around the center carbon atom makes the entire molecule asymmetrical in shape. The center carbon atom is referred to as the chiral center.
For a particular compound, two mirror-image stereoisomer forms, called enantiomers, can occur around the chiral center. Each enantiomer demonstrates either a “right-handed” or “left-handed” orientation. The most concrete example of this phenomenon is to consider the similarities and differences between the right and left hands of the human body. Each hand has an exactly similar composition and structure in space, but they are different with respect to their spatial orientation. Each hand is a mirror image of the other, but they cannot be superimposed. For this reason, a left hand cannot fit into a right-handed glove and vice versa.
Most chemical reactions that are not biological in origin produce chiral molecules with both mirror-image enantiomers occurring in equal proportions. This combined form is referred to as a racemic mixture or racemate. By contrast, naturally occurring chemical reactions tend to produce only one enantiomer form. Molecules that are essential for life occur in only one enantiomer form. For example, most proteins are formed of “left-handed” natural amino acids, whereas most carbohydrates are composed of “right-handed” natural sugars.
Describing Enantiomers and Diastereomers
Enantiomers cannot be separated by the usual methods of purifying chemical compounds (e.g., distillation, crystallization, chromatography) because their physical properties (e.g., melting point, boiling point) are similar. One difference between enantiomers, however, is how they rotate plane-polarized light. Compounds that rotate polarized light clockwise are called dextrorotatory; those that rotate polarized light counterclockwise are termed levorotatory. Dextrorotatory compounds are designated with the (+) descriptor in their chemical names; levorotatory compounds are designated with the (–) symbol. The (+) and (–) isomers also are referred to as d- (for dextrorotatory) and l- (for levorotatory) isomers, respectively. Racemic mixtures will usually not rotate plane-polarized light because the different optical properties of the constituent enantiomers will cancel each other out.
In addition to the optical properties of enantiomers, another way of describing the three-dimensional configuration of enantiomers is referred to as the Cahn-Ingold-Prelog (CIP) convention. The CIP convention assigns a priority score to each of the four substituent groups that surround the carbon chiral center. The priority score is based on the relative atomic number (taken from the periodic table of elements) of the atom or the chain of atoms that comprise the substituent group. Higher priority scores are given to substituent groups having relatively higher atomic numbers. When priority scores have been assigned to each of the four substituent groups, the entire molecule can then be visualized in an orientation such that the lowest-priority substituent group is situated in the line of sight directly behind the carbon chiral center. If the remaining three substituent groups are then visualized and they decrease in their priority score around the chiral center in a clockwise direction, the substance is designated as the R (rectus, Latin for “right”) enantiomer. If the direction is counterclockwise, the substance is designated as an S (sinister, Latin for “left”) enantiomer. A chiral substance is therefore described by its stereochemical CIP descriptor (R, S) and optical properties (+, –), as well as by its chemical name.
Amino acids, carbohydrates, and carbohydrate-like molecules or compounds are described somewhat differently (referred to as the Fischer convention). According to the Fischer convention, stereoisomer configurations of amino acids and carbohydrates are described using the descriptors D- and L-. These descriptors are assigned by comparing the compound with a standard reference molecule (glyceraldehyde). Glyceraldehyde is a kind of sugar (often occurring as an intermediate compound during carbohydrate metabolism) that exists as two enantiomers, D-glyceraldehyde and L-glyceraldehyde. If the molecule has the same configuration as D-glyceraldehyde, it is assigned the D- configuration; molecules with the same configuration as L-glyceraldehyde are assigned the L- configuration.
Diastereomers are more complicated molecular compounds that include all stereoisomers that are not mirror images of one another. Unlike enantiomers, diastereomers have different physical properties and can be separated or purified using typical chemical methods. Similar to enantiomers, however, diastereomers can have different pharmacological, biological, and clinical effects. Isomers of compounds in which atoms and substituent groups are arranged asymmetrically around a carbon-carbon double bond are also diastereomers. Because the carbon atoms connected by a double-bond cannot rotate (as they could if connected by a single bond), the diastereomers of double-bond compounds are designated as cis- or trans-. This designation depends on which side (cis- [same side] or trans- [opposite side]) the substituent groups are attached to the atoms at either end of the double bond. If a cis/trans diastereomer compound has a chiral carbon, each isomer may also have enantiomers. In other words, the cis- and trans- diastereomers are not mirror images of each other, but the cis-diastereomer may have two mirror image enantiomers, and the trans-diastereomer may as well.
Chiral Drugs and Chiral Switches
Historically, most drugs with a carbon chiral center were developed and marketed for pharmaceutical use as racemic mixtures of enantiomers. One reason for this was the relative lack of awareness of the potential clinical implications of the different pharmacological properties of enantiomers. Also, although enantiomers can be identified, the actual separation and purification of single enantiomers is technically challenging. In 1992, the U.S. Food and Drug Administration (FDA) published formal guidelines that encouraged the investigation and development of drugs on the basis of their stereoisomer properties. As a result, more attention has been paid to understanding the pharmacological and clinical relevance of the individual enantiomers of racemic drugs, and more single-enantiomer drugs have been developed.
The presence of a second enantiomer in racemic mixtures can be associated with various potential problems. The second enantiomer may be less biologically active but can still interfere with the more biologically active enantiomer by binding to the same site. Adverse reactions can sometimes be attributed to one of the enantiomers. Each enantiomer may bind to metabolic enzymes differently, resulting in different rates of metabolism and clearance. They also may have different interactions with other drugs.
When a pharmaceutical manufacturer develops a single-enantiomer product from a drug marketed as a racemic mixture, it referred to as a chiral switch. The single-enantiomer product is given a new generic name (based on rules for naming enantiomers) and receives additional patent protection. The manufacturer markets the single-enantiomer drug as a new product, with a different trade name.
Although single-enantiomer drugs may be developed for scientifically sound clinical reasons, chiral switches can be used by manufacturers simply to extend the marketing lifetime of a drug. The investigation, development, and use of stereochemically pure drugs, however, was recommended by the FDA in its 1992 guidelines, with the goal of improving the therapeutic index (efficacy, tolerability, safety, pharmacokinetics, and drug-drug interactions) of marketed drugs. The value of specific enantiomeric switches has sometimes been debated, but the general concept is valid. Although chirality and stereochemistry are seemingly arcane, nurses should try to understand and appreciate these concepts, which are highly relevant for understanding new developments in clinical psychopharmacology, as well as explaining real and potential problems with particular drug therapies. Examples of drug therapies that exemplify the clinical relevance of these concepts will be reviewed in next month’s article.