Steric Features Of Drugs

Regardless of the ultimate mechanism by which the drug and the receptor interact, the drug must approach the receptor and fit closely to its surface. Steric factors determined by the stereochemistry of the receptor site surface and that of the drug molecules are, therefore, of primary importance in determining the nature and the efficiency of the drug-receptor interaction. With the possible exception of the general anesthetics, such drugs must possess a high structural specificity to initiate a response at a particular receptor.

Some structural features contribute a high structural rigidity to the molecule. For example, aromatic rings are planar, and the atoms attached directly to these rings are held in the plane of the aromatic ring. Hence, the quaternary

Neostigmine nitrogen and carbamate oxygen attached directly to the benzene ring in the cholinesterase inhibitor neostigmine are restricted to the plane of the ring, and consequently, the spatial arrangement of at least these atoms is established.

The relative positions of atoms attached directly to multiple bonds are also fixed. For the double bond, cis- and trans-isomers result. For example, diethylstilbestrol exists in two fixed stereoisomeric forms: trans-diethylstilbestrol is estrogenic, whereas the cis-isomer is only 7% as active. In trans-diethylstilbestrol, resonance interactions and minimal steric interference tend to hold the two aromatic rings and connecting ethylene carbon atoms in the same plane.

Cefprozil Structure Cis Trans Isomers

Geometric isomers, such as the cis- and the trans-isomers, hold structural features at different relative positions in space. These isomers also have significantly different physical and chemical properties. Therefore, their distributions in the biological medium are different, as are their capabilities for interacting with a biological receptor in a structurally specific manner. The United States Pharmacopeia recognizes that there are drugs with vinyl groups whose commercial form contains both their E- and Z-isomers. Figure 2.13 provides four examples of these mixtures.

More subtle differences exist for conformational isomers. Like geometric isomers, these exist as different arrangements in space for the atoms or groups in a single classic structure. Rotation about bonds allows interconversion of conformational isomers. However, an energy barrier between isomers is often high enough for their independent existence and reaction. Differences in reactivity of functional groups or interaction with biological receptors may be caused by differences in steric requirements of the receptors. In certain semirigid ring systems, conformational isomers show significant differences in biological activities. Methods for calculating these energy barriers are described next.

Open chains of atoms, which form an important part of many drug molecules, are not equally free to assume all possible conformations; some are sterically preferred. Energy barriers to free rotation of the chains are present because of interactions of nonbonded atoms. For example, the atoms tend to position themselves in space so that they occupy staggered positions, with no two atoms directly facing each other (eclipsed). Nonbonded interactions in polymethylene

S Xs, c2h5

S Xs, c2h5


C2H5 CH2 o


Z-Doxepin: ra = ch2ch2n(ch3)2; r2 = h E-Doxepin: R^ = h; r2 = ch2ch2n(ch3)2

Figure 2.13

Cefprozil Molecule

Z-Cefprozil: R^ = h; r2 = ch3 E-Cefprozil: R^ = ch3; r2 = h

Examples of E- and Z-isomers.

Acetylcholine Eclipsed Form

Stabilized planar structure of amides

Figure 2.14 • Effect of noncarbon atoms on a molecule's configuration.

Stabilized planar structure of amides

Figure 2.14 • Effect of noncarbon atoms on a molecule's configuration.

chains tend to favor the most extended anti conformations, although some of the partially extended gauche conformations also exist. Intramolecular bonding between substituent groups can make what might first appear to be an unfavorable conformation favorable.

The introduction of atoms other than carbon into a chain strongly influences the conformation of the chain (Fig. 2.14). Because of resonance contributions of forms in which a double bond occupies the central bonds of esters and amides, a planar configuration is favored in which minimal steric interference of bulky substituents occurs. Hence, an ester may exist mainly in the anti, rather than the gauche, form. For the same reason, the amide linkage is essentially planar, with the more bulky substituents occupying the anti position. Therefore, ester and amide linkages in a chain tend to hold bulky groups in a plane and to separate them as far as possible. As components of the side chains of drugs, ester and amide groups favor fully extended chains and also add polar character to that segment of the chain.

In some cases, dipole-dipole interactions appear to influence structure in solution. Methadone may exist partially in a cyclic form in solution because of dipolar attractive forces between the basic nitrogen and carbonyl group or because of hydrogen bonding between the hydrogen on the nitrogen and the carbonyl oxygen (Fig. 2.15). In either conformation, methadone may resemble the conformationally more rigid potent analgesics including morphine, meperidine, and their analogs (see Chapter 24), and it may be this form that interacts with the analgesic receptor. Once the interaction between the drug and its receptor begins, a flexible drug molecule may assume a different conformation than that predicted from solution chemistry.

An intramolecular hydrogen bond usually formed between donor hydroxy and amino groups and acceptor oxygen and nitrogen atoms, might be expected to add stability to a particular conformation of a drug in solution. However, in aqueous solution, donor and acceptor groups tend to be bonded to water, and little gain in free energy would be achieved by the formation of an intramolecular hydrogen bond, particularly if unfavorable steric factors involving nonbonded interactions were introduced in the

Figure 2.15 • Stabilization of conformations by secondary bonding forces.

process. Therefore, internal hydrogen bonds likely play only a secondary role to steric factors in determining the conformational distribution of flexible drug molecules.

Hydrogen-bonding donor groups

R2 R3

Hydrogen - bond/ng acceptor groups

Conformational Flexibility and Multiple Modes of Action

It has been proposed that the conformational flexibility of most open-chain neurohormones, such as acetylcholine, epinephrine, serotonin, histamine, and related physiologically active biomolecules, permits multiple biological effects to be produced by each molecule, by virtue of their ability to interact in a different and unique conformation with different biological receptors. Thus, it has been suggested that acetylcholine may interact with the muscarinic receptor of postganglionic parasympathetic nerves and with acetylcholinesterase in the fully extended conforma tion and, in a different, more folded structure, with the nicotinic receptors at ganglia and at neuromuscular junctions (Fig. 2.16).

Conformationally rigid acetylcholine-like molecules have been used to study the relationships between these various possible conformations of acetylcholine and their biological effects (Fig. 2.16). (+)-trans-2-Acetoxycyclopropyl trimethylammonium iodide, in which the quaternary nitrogen atom and acetoxyl groups are held apart in a conformation approximating that of the extended conformation of acetylcholine, was about five times more active than acetyl-choline in its muscarinic effect on dog blood pressure and was as active as acetylcholine in its muscarinic effect on the guinea pig ileum.18 The (+)-trans-isomer was hydrolyzed by acetylcholinesterase at a rate equal to the rate of hydrolysis of acetylcholine. It was inactive as a nicotinic agonist. In contrast, the (—)-trans-isomer and the mixed (±)-cis-iso-mers were, respectively, 1/500 and 1/10,000 as active as acetylcholine in muscarinic tests on guinea pig ileum and were inactive as nicotinic agonists. Similarly, the trans diax-ial relationship between the quaternary nitrogen and ace-toxyl group led to maximal muscarinic response and rate of hydrolysis by true acetylcholinesterase in a series of iso-meric 3-trimethylammonium-2-acetoxydecalins.19 These results could be interpreted as either that acetylcholine was acting in a trans conformation at the muscarinic receptor and not acting in a cisoid conformation at the nicotinic receptor or that the nicotinic response is highly sensitive to steric effects of substituents being used to orient the

Figure 2.16 • Acetylcholine conformations (only one each of the two possible transand c/s-isomers is represented).

Figure 2.16 • Acetylcholine conformations (only one each of the two possible transand c/s-isomers is represented).

Stereoisomers Acetylcholine

molecule. This approach in studying the cholinergic receptor is covered in more detail in Chapter 17.

Optical Isomerism and Biological Activity

The widespread occurrence of differences in biological activities for optical activities has been of particular importance in the development of theories on the nature of drug-receptor interactions. Most commercial drugs are asymmetric, meaning that they cannot be divided into symmetrical halves. Although d- and l-isomers have the same physical properties, a large number of drugs are diastereomeric, meaning that they have two or more asymmetric centers. Diastereomers have different physical properties. Examples are the diastereomers ephedrine and pseudoephedrine. The former has a melting point of 79° and is soluble in water, whereas pseudoephedrine's melting

point is 118°, and it is only sparingly soluble in water. Keep in mind that receptors will be asymmetric because they are mostly protein, meaning that they are constructed from lamino acids. A ligand fitting the hypothetical receptor shown in Figure 2.18 will have to have a positively charged moiety in the upper left corner and a hydrophobic region in the upper right. Therefore, one would predict that optical isomers will also have different biological properties. Well-known examples of this phenomenon include ( —)-hyoscyamine, which exhibits 15 to 20 times more mydriatic activity than ( + )-hyoscy amine, and ( — )-ephedrine, which shows three times more pressor activity than (+)-ephedrine, five times more pressor activity than (+)-pseudoephedrine, and 36 times more pressor activity than ( — ^pseudoephedrine. All of ascorbic acid's antiscorbutic properties reside in the (+) isomer. A postulated fit to epinephrine's receptor can explain why ( — )-epinephrine exhibits 12 to 15 times more vasoconstrictor activity than (+)-epinephrine. This is the classical three-point attachment model. For epinephrine, the benzene ring, benzylic hydroxyl, and proto-nated amine must have the stereochemistry seen with the ( —) isomer to match up with the hydrophobic or aromatic region, anionic site, and a hydrogen-bonding center on the receptor. The (+) isomer (the mirror image) will not align properly on the receptor.

Frequently, the generic name indicates a specific stereoisomer. Examples include levodopa, dextroamphetamine, dextromethorphan, levamisole, dexmethylphenidate, levobupivacaine, dexlansoprazole, and levothyroxine. Sometimes, the difference in pharmacological activity between stereoisomers is dramatic. The dextrorotatory isomers in the morphine series are cough suppressants with less risk of substance abuse, whereas the levorotatory isomers (Fig. 2.19) contain the analgesic activity and significant risk of substance abuse. Although the direction of optical rotation is opposite to that of the morphine series, dextropropoxyphene contains the analgesic activity, and the levo-isomer contains antitussive activity. More recently drugs originally marketed as racemic mixtures are reintroduced using the active isomer. The generic name of the latter does not readily indicate that the new product is a specific stereoisomer of a product already in use. Examples include racemic citalo-pram and its S-enantiomer escitalopram; racemic omeprazole and its S-enantiomer esomeprazole; and racemic modafinil and its R-enantiomer armodafinil.

Figure 2.17 contains examples of drugs with asymmetric carbons. Some were originally approved as racemic mixtures, and later a specific isomer was marketed with claims of having fewer adverse reactions in patients. An example of the latter is the local anesthetic levobupivacaine, which is the ^-isomer of bupivacaine. Both the R- and ^-isomers have good local anesthetic activity, but the R-isomer may cause depression of the myocardium leading to decreased cardiac output, heart block hypotension, bradycardia, and ventricular arrhythmias. In contrast, the ^-isomer shows less cardiotoxic responses but still good local anesthetic activity. Escitalopram is the ^-isomer of the antidepressant citalo-pram. There is some evidence that the R-isomer, which contains little of the desired selective serotonin reuptake inhibition, contributes more to the adverse reactions than does the ^-isomer.

As dramatic as the previous examples of stereoselectivity may be, sometimes it may not be cost-effective to resolve

Stereoisomers Acetylcholine

Figure 2.17 • Examples of drug stereoisomers.

the drug into its stereoisomers. An example is the calcium channel antagonist verapamil, which illustrates why it is difficult to conclude that one isomer is superior to the other. S-Verapamil is a more active pharmacological stereoisomer than ^-verapamil, but the former is more rapidly metabolized by the first-pass effect. First-pass refers to orally administered drugs that are extensively metabolized as they pass through the liver (see Chapter 3). S- and ^-warfarin are metabolized by two different cytochrome P450 isozymes. Drugs that either inhibit or induce these enzymes can significantly affect warfarin's anticoagulation activity.

Because of biotransformations after the drug is administered, it sometimes makes little difference whether a racemic mixture or one isomer is administered. The popular nonsteroidal anti-inflammatory drug (NSAID) ibuprofen is sold as the racemic mixture. The S-enantiomer contains the anti-inflammatory activity by inhibiting cyclooxygenase. The ^-isomer does have centrally acting analgesic activity, but it is converted to the S form in vivo (Fig. 2.18).

In addition to the fact that most receptors are asymmetric, there are other reasons why stereoisomers show different biological responses. Active transport mechanisms involve asymmetric carrier molecules, which means that there will be preferential binding of one stereoisomer over others. When differences in physical properties exist, the distribution of isomers between body fluids and tissues where the receptors are located will differ. The enzymes responsible for drug metabolism are asymmetric, which means that biological half-lives will differ among possible stereoisomers of the same molecule. The latter may be a very important variable because the metabolite may actually be the active molecule.

Stereoisomers Acetylcholine


Figure 2.18 • Metabolic interconversion of R- and S-ibuprofen.

Calculated Conformations

It should now be obvious that medicinal chemists must obtain an accurate understanding of the active conformation of the drug molecule. Originally, molecular models were constructed from kits containing various atoms of different valence and oxidation states. Thus, there would be carbons suitable for carbon-carbon single, double, and triple bonds; carbon-oxygen bonds for alcohols or ethers and the car-bonyl moiety; carbon-nitrogen bonds for amines, amides, imines, and nitrites; and carbons for three-, four-, five-, and larger-member rings. More complete sets include various heteroatoms including nitrogen, oxygen, and sulfur in various oxidation states. These kits might be ball and stick, stick or wire only, or space filling. The latter contained attempts at realistically visualizing the effect of a larger atom such as sulfur relative to the smaller oxygen. The diameters of the atoms in these kits are proportional to the van der Waals radii, usually corrected for overlap effects. In contrast, the wire models usually depict accurate intra-atomic distances between atoms. A skilled chemist using these kits usually can obtain a reasonably accurate 3D representation. This is particularly true if it is a moderately simple molecule with considerable rigidity. An extreme example is a steroid with the relatively inflexible fused-ring system. In contrast, molecules with chains consisting of several atoms can assume many shapes. Yet, there will be a best shape or conformation that can be expected to fit onto the receptor. The number of conformers can be estimated from Equation 2.17. Calculating the global minimum, the lowest-energy conformation, can be a difficult computational problem. Assume that there are three carbon-carbon freely rotatable single bonds that are rotated in 10-degree increments. Equation 2.17 states that there are 46,656 different conformations.

Number of conformers =

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