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Pharmacologic Response

The ideal drug molecule will show favorable binding characteristics to the receptor, and the equilibrium will lie to the right. At the same time, the drug will be expected to dissociate from the receptor and reenter the systemic circulation to be excreted. Major exceptions include the alkylating agents used in cancer chemotherapy (see Chapter 10), a few inhibitors of the enzyme acetylcholinesterase (see Chapter 17), suicide inhibitors of monoamine oxidase (see Chapter 16), and the aromatase inhibitors 4-hydrox-yandrostenedione and exemestane (see Chapter 25). These pharmacological agents form covalent bonds with the receptor, usually an enzyme's active site. In these cases, the cell must destroy the receptor or enzyme, or, in the case of the alkylating agents, the cell would be replaced, ideally with a normal cell. In other words, the usual use of drugs in medical treatment calls for the drug's effect to last for a finite period of time. Then, if it is to be repeated, the drug will be administered again. If the patient does not tolerate the drug well, it is even more important that the agent dissociate from the receptor and be excreted from the body.

Oral Administration

An examination of the obstacle course (Fig. 2.1) faced by the drug will give a better understanding of what is involved in developing a commercially feasible product. Assume that the drug is administered orally. The drug must go into solution to pass through the gastrointestinal mucosa. Even drugs administered as true solutions may not remain in solution as they enter the acidic stomach and then pass into the alkaline intestinal tract. (This is explained further in the discussion on acid-base chemistry.) The ability of the drug to dissolve is governed by several factors, including its chemical structure, variation in particle size and particle surface area, nature of the crystal form, type of tablet coating, and type of tablet matrix. By varying the dosage form and physical characteristics of the drug, it is possible to have a drug dissolve quickly or slowly, with the latter being the situation for many of the sustained-action products. An example is orally administered sodium phenytoin, with which variation of both the crystal form and tablet adjuvants can significantly alter the bioavailability of this drug widely used in the treatment of epilepsy.

Chemical modification is also used to a limited extent to facilitate a drug reaching its desired target (see Chapter 3). An example is olsalazine, used in the treatment of ulcera-tive colitis. This drug is a dimer of the pharmacologically active mesalamine (5-aminosalicylic acid). The latter is not effective orally because it is metabolized to inactive forms before reaching the colon. The dimeric form passes

Drug must pass through membranes. -----Drug administered directly into systemic circulation.

Figure 2.1 • Summary of drug distribution.

through a significant portion of the intestinal tract before being cleaved by the intestinal bacteria to two equivalents of mesalamine.

As illustrated by olsalazine, any compound passing through the gastrointestinal tract will encounter a large number and variety of digestive and bacterial enzymes, which, in theory, can degrade the drug molecule. In practice, a new drug entity under investigation will likely be dropped from further consideration if it cannot survive in the intestinal tract or its oral bioavailability is low, necessitating parenteral dosage forms only. An exception would be a drug for which there is no effective alternative or which is more effective than existing products and can be administered by an alternate route, including parenteral, buccal, or transdermal.

In contrast, these same digestive enzymes can be used to advantage. Chloramphenicol is water soluble enough

(2.5 mg/mL) to come in contact with the taste receptors on the tongue, producing an unpalatable bitterness. To mask this intense bitter taste, the palmitic acid moiety is added as an ester of chloramphenicol's primary alcohol. This reduces the parent drug's water solubility (1.05 mg/mL), enough so that it can be formulated as a suspension that passes over the bitter taste receptors on the tongue. Once in the intestinal tract, the ester linkage is hydrolyzed by the digestive esterases to the active antibiotic chloramphenicol and the very common dietary fatty acid palmitic acid.

Olsalazine and chloramphenicol palmitate are examples of prodrugs. Most prodrugs are compounds that are inactive in their native form but are easily metabolized to the active agent. Olsalazine and chloramphenicol palmitate are examples of prodrugs that are cleaved to smaller compounds, one of which is the active drug. Others are metabolic precursors to the active form. An example of this type of prodrug is menadione, a simple naphthoquinone that is converted in the liver to phytonadione (vitamin K2(20)).

Occasionally, the prodrug approach is used to enhance the absorption of a drug that is poorly absorbed from the gastrointestinal tract. Enalapril is the ethyl ester of enalaprilic acid, an active inhibitor of angiotensin-converting enzyme (ACE). The ester prodrug is much more readily absorbed orally than the pharmacologically active carboxylic acid.

Unless the drug is intended to act locally in the gastrointestinal tract, it will have to pass through the gastrointestinal mucosal barrier into venous circulation to reach the site of the receptor. The drug's route involves distribution or partitioning between the aqueous environment of the gastrointestinal tract, the lipid bilayer cell membrane of the mucosal cells, possibly the aqueous interior of the mucosal cells, the lipid bilayer membranes on the venous side of the gastrointestinal tract, and the aqueous environment of venous circulation. Some very lipid-soluble drugs may follow the route of dietary lipids by becoming part of the mixed micelles, incorporating into the chylomicrons in the mucosal cells into the lymph ducts, servicing the intestines, and finally entering venous circulation via the thoracic duct.

The drug's passage through the mucosal cells can be passive or active. As is discussed later in this chapter, the lipid membranes are very complex with a highly ordered structure. Part of this membrane is a series of channels or tunnels that form, disappear, and reform. There are receptors that move compounds into the cell by a process called pinocytosis. Drugs that resemble a normal metabolic precursor or intermediate may be actively transported into the cell by the same system that transports the endogenous compound. On the other hand, most drug molecules are too large to enter the cell by an active transport mechanism through the passages. The latter, many times, pass into the patient's circulatory system by passive diffusion.

Parenteral Administration

Many times, there will be therapeutic advantages in bypassing the intestinal barrier by using parenteral (injectable) dosage forms. This is common in patients who, because of illness, cannot tolerate or are incapable of accepting drugs orally. Some drugs are so rapidly and completely metabolized to inactive products in the liver (first-pass effect) that oral administration is precluded. But that does not mean that the drug administered by injection is not confronted by obstacles (Fig. 2.1). Intravenous administration places the drug directly into the circulatory system, where it will be rapidly distributed throughout the body, including tissue depots and the liver, where most biotransformations occur (see later in this chapter), in addition to the receptors. Subcutaneous and intramuscular injections slow distribution of the drug, because it must diffuse from the site of injection into systemic circulation.

It is possible to inject the drug directly into specific organs or areas of the body. Intraspinal and intracerebral routes will place the drug directly into the spinal fluid or brain, respectively. This bypasses a specialized epithelial tissue, the blood-brain barrier, which protects the brain from exposure to a large number of metabolites and chemicals. The blood-brain barrier is composed of membranes of tightly joined epithelial cells lining the cerebral capillaries. The net result is that the brain is not exposed to the same variety of compounds that other organs are. Local anesthetics are examples of administration of a drug directly onto the desired nerve. A spinal block is a form of anesthesia performed by injecting a local anesthetic directly into the spinal cord at a specific location to block transmission along specific neurons.

Most of the injections a patient will experience in a lifetime will be subcutaneous or intramuscular. These parenteral routes produce a depot in the tissues (Fig. 2.1), from which the drug must reach the blood or lymph. Once in systemic circulation, the drug will undergo the same distributive phenomena as orally and intravenously administered agents before reaching the target receptor. In general, the same factors that control the drug's passage through the gastrointestinal mucosa will also determine the rate of movement out of the tissue depot.

The prodrug approach described previously can also be used to alter the solubility characteristics, which, in turn, can increase the flexibility in formulating dosage forms. The solubility of methylprednisolone can be altered from essentially water-insoluble methylprednisolone acetate to slightly water-insoluble methylprednisolone to water-soluble methylprednisolone sodium succinate. The water-soluble sodium hemisuccinate salt is used in oral, intravenous, and intramuscular dosage forms. Methylprednisolone itself is normally found in tablets. The acetate ester is found in topical ointments and sterile aqueous suspensions for intramuscular injection. Both the succinate and acetate esters are hydrolyzed to the active methylprednisolone by the patient's own systemic hydrolytic enzymes (esterases).

Methylprednisolone: R = H Methylprednisolone Acetate: R = C(=0)CH3

Methylprednisolone Sodium Succinate: R = C(=0)CH2CH2C00" Na+

Methylprednisolone: R = H Methylprednisolone Acetate: R = C(=0)CH3

Methylprednisolone Sodium Succinate: R = C(=0)CH2CH2C00" Na+

Another example of how prodrug design can significantly alter biodistribution and biological half-life is illustrated by two drugs based on the retinoic acid structure used systemi-cally to treat psoriasis, a nonmalignant hyperplasia. Etretinate has a 120-day terminal half-life after 6 months of therapy. In contrast, the active metabolite, acitretin, has a 33- to 96-hour terminal half-life. Both drugs are potentially teratogenic. Women of childbearing age must sign statements that they are aware of the risks and usually are administered a pregnancy test before a prescription is issued. Acitretin, with its shorter half-life, is recommended for a woman who would like to become pregnant, because it can clear her body within a reasonable time frame. When effective, etretinate can keep a patient clear of psoriasis lesions for several months.

Protein Binding

Once the drug enters the systemic circulation (Fig. 2.1), it can undergo several events. It may stay in solution, but many drugs will be bound to the serum proteins, usually albumin (Rx. 2.2). Thus, a new equilibrium must be considered. Depending on the equilibrium constant, the drug can remain in systemic circulation bound to albumin for a considerable period and not be available to the sites of biotransformation, the pharmacological receptors, and excretion.

Protein binding can have a profound effect on the drug's effective solubility, biodistribution, half-life in the body, and interaction with other drugs. A drug with such poor water solubility that therapeutic concentrations of the unbound (active) drug normally cannot be maintained still can be a very effective agent. The albumin-drug complex acts as a reservoir by providing large enough concentrations of free drug to cause a pharmacological response at the receptor.

Protein binding may also limit access to certain body compartments. The placenta is able to block passage of proteins from maternal to fetal circulation. Thus, drugs that normally would be expected to cross the placental barrier and possibly harm the fetus are retained in the maternal circulation, bound to the mother's serum proteins.

Protein binding also can prolong the drug's duration of action. The drug-protein complex is too large to pass through the renal glomerular membranes, preventing rapid excretion of the drug. Protein binding limits the amount of drug available for biotransformation (see later in this chapter and Chapter 3) and for interaction with specific receptor sites. For

Suramin Sodium

example, the large, polar trypanocide suramin remains in the body in the protein-bound form for as long as 3 months (ti/2 = 50 days). The maintenance dose for this drug is based on weekly administration. At first, this might seem to be an advantage to the patient. It can be, but it also means that, should the patient have serious adverse reactions, a significant length of time will be required before the concentration of drug falls below toxic levels.

The drug-protein binding phenomenon can lead to some clinically significant drug-drug interactions that result when one drug displaces another from the binding site on albumin. A large number of drugs can displace the anticoagulant warfarin from its albumin-binding sites. This increases the effective concentration of warfarin at the receptor, leading to an increased prothrombin time (increased time for clot formation) and potential hemorrhage.

Tissue Depots

The drug can also be stored in tissue depots. Neutral fat constitutes some 20% to 50% of body weight and constitutes a depot of considerable importance. The more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots. The ultra-short-acting, lipophilic barbiturate thiopental's concentration rapidly decreases below its effective concentration following administration. It disappears into tissue protein, redistributes into body fat, and then slowly diffuses back out of the tissue depots but in concentrations too low for a pharmacological response. Thus, only the initially administered thiopental is present in high enough concentrations to combine with its receptors. The remaining thiopental diffuses out of the tissue depots into systemic circulation in concentrations too small to be effective (Fig. 2.1), is metabolized in the liver, and is excreted.

In general, structural changes in the barbiturate series (see Chapter 12) that favor partitioning into the lipid tissue stores decrease duration of action but increase central nervous system (CNS) depression. Conversely, the barbiturates with the slowest onset of action and longest duration of action contain the more polar side chains. This latter group of barbiturates both enters and leaves the CNS more slowly than the more lipophilic thiopental.

Drug Metabolism

All substances in the circulatory system, including drugs, metabolites, and nutrients, will pass through the liver. Most molecules absorbed from the gastrointestinal tract enter the portal vein and are initially transported to the liver. A significant proportion of a drug will partition or be transported into the hepatocyte, where it may be metabolized by hepatic enzymes to inactive chemicals during the initial trip through the liver, by what is known as the firstpass effect (see Chapter 3).

Lidocaine is a classic example of the significance of the first-pass effect. Over 60% of this local anesthetic antiar-rhythmic agent is metabolized during its initial passage through the liver, resulting in it being impractical to administer orally. When used for cardiac arrhythmias, it is administered intravenously. This rapid metabolism of lidocaine is used to advantage when stabilizing a patient with cardiac arrhythmias. Should too much lidocaine be administered intravenously, toxic responses will tend to decrease because of rapid biotransformation to inactive metabolites. An understanding of the metabolic labile site on lidocaine led to the development of the primary amine analog tocainide. In contrast to lidocaine's half-life of less than 2 hours, tocainide's half-life is approximately 15 hours, with 40% of the drug excreted unchanged. The development of orally active antiarrhythmic agents is discussed in more detail in Chapter 19.

A study of the metabolic fate of a drug is required for all new drug products. Often it is found that the metabolites are also active. Sometimes the metabolite is the pharmacologically active molecule. These drug metabolites can provide leads for additional investigations of potentially new products. Examples of an inactive parent drug that is converted to an active metabolite include the nonsteroidal anti-inflammatory agent sulindac being reduced to the active sulfide metabolite, the immunosuppressant azathioprine being cleaved to the purine antimetabolite 6-mercaptopurine, and purine and pyrimidine antimetabolites and antiviral agents being conjugated to their nucleotide form (acyclovir phosphorylated to acyclovir triphosphate). Often both the parent drug and its metabolite are active, which has led to additional commercial products, instead of just one being marketed. About 75% to 80% of phenacetin (now withdrawn from the U.S. market) is converted to acetaminophen. In the tricyclic antidepressant series (see Chapter 12), imipramine and amitriptyline are N-demethylated to desipramine and nortriptyline, respectively. All four compounds have been marketed in the United States. Drug metabolism is discussed more fully in Chapter 3.

Although a drug's metabolism can be a source of frustration for the medicinal chemist, pharmacist, and physician and lead to inconvenience and compliance problems with the patient, it is fortunate that the body has the ability to metabolize foreign molecules (xenobiotics). Otherwise, many of these substances could remain in the body for years. This has been the complaint against certain lipophilic chemical pollutants, including the once very popular insecticide dichlorodiphenyltrichloroethane (DDT). After entering the body, these chemicals reside in body tissues, slowly diffusing out of the depots and potentially harming the individual on a chronic basis for several years. They can also reside in tissues of commercial food animals that have been slaughtered before the drug has washed out of the body.


The main route of excretion of a drug and its metabolites is through the kidney. For some drugs, enterohepatic circulation (Fig. 2.1), in which the drug reenters the intestinal tract from the liver through the bile duct, can be an important part of the agent's distribution in the body and route of excretion. Either the drug or drug metabolite can reenter systemic circulation by passing once again through the intestinal mucosa. A portion of either also may be excreted in the feces. Nursing mothers must be concerned, because drugs and their metabolites can be excreted in human milk and be ingested by the nursing infant.

One should keep a sense of perspective when learning about drug metabolism. As explained in Chapter 3, drug metabolism can be conceptualized as occurring in two stages or phases. Intermediate metabolites that are pharmacologically active usually are produced by phase I reactions. The products from the phase I chemistry are converted into inactive, usually water-soluble end products by phase II reactions. The latter, commonly called conjugation reactions, can be thought of as synthetic reactions that involve addition of water-soluble substituents. In human drug metabolism, the main conjugation reactions add glucuronic acid, sulfate, or glutathione. Obviously, drugs that are bound to serum protein or show favorable partitioning into tissue depots are going to be metabolized and excreted more slowly for the reasons discussed previously.

This does not mean that drugs that remain in the body for longer periods of time can be administered in lower doses or be taken fewer times per day by the patient. Several variables determine dosing regimens, of which the affinity of the drug for the receptor is crucial. Reexamine Reaction 2.1 and Figure 2.1. If the equilibrium does not favor formation of the drug-receptor complex, higher and usually more frequent doses must be administered. Further, if partitioning into tissue stores or metabolic degradation and/or excretion is favored, it will take more of the drug and usually more frequent administration to maintain therapeutic concentrations at the receptor.

The Receptor

With the possible exception of general anesthetics (see Chapter 22), the working model for a pharmacological response consists of a drug binding to a specific receptor. Many drug receptors are the same as those used by endoge-nously produced ligands. Cholinergic agents interact with the same receptors as the neurotransmitter acetylcholine.

Synthetic corticosteroids bind to the same receptors as cortisone and hydrocortisone. Often, receptors for the same li-gand are found in various tissues throughout the body. The nonsteroidal anti-inflammatory agents (see Chapter 26) inhibit the prostaglandin-forming enzyme cyclooxygenase, which is found in nearly every tissue. This class of drugs has a long list of side effects with many patient complaints. Note in Figure 2.1 that, depending on which receptors contain bound drug, there may be desired or undesired effects. This is because various receptors with similar structural requirements are found in several organs and tissues. Thus, the nonsteroidal anti-inflammatory drugs combine with the desired cyclooxygenase receptors at the site of the inflammation and the undesired cyclooxygenase receptors in the gastrointestinal mucosa, causing severe discomfort and sometimes ulceration. One of the second-generation antihis-tamines, fexofenadine, is claimed to cause less sedation because it does not readily penetrate the blood-brain barrier. The rationale is that less of this antihistamine is available for the receptors in the CNS, which are responsible for the sedation response characteristic of antihistamines. In contrast, some antihistamines are used for their CNS depressant activity because a significant proportion of the administered dose is crossing the blood-brain barrier relative to binding to the histamine H1 receptors in the periphery.

Although it is normal to think of side effects as undesirable, they sometimes can be beneficial and lead to new products. The successful development of oral hypoglycemic agents used in the treatment of diabetes began when it was found that certain sulfonamides had a hypoglycemic effect. Nevertheless, a real problem in drug therapy is patient compliance in taking the drug as directed. Drugs that cause serious problems and discomfort tend to be avoided by patients.

At this point, let us assume that the drug has entered the systemic circulation (Fig. 2.1), passed through the lipid barriers, and is now going to make contact with the receptor. As illustrated in Reaction 2.1, this is an equilibrium process. A good ability to fit the receptor favors binding and the desired pharmacological response. In contrast, a poor fit favors the reverse reaction. With only a small amount of drug bound to the receptor, there will be a much smaller pharmacological effect. If the amount of drug bound to the receptor is too small, there may be no discernible response. Many variables contribute to a drug's binding to the receptor. These include the structural class, the 3D shape of the molecule, and the types of chemical bonding involved in the binding of the drug to the receptor.

Most drugs that belong to the same pharmacological class have certain structural features in common. The barbiturates act on specific CNS receptors, causing depressant effects; hydantoins act on CNS receptors, producing an anticonvulsant response; benzodiazepines combine with the y-aminobutyric acid (GABA) receptors, with resulting anxiolytic activity; steroids can be divided into such classes as corticosteroids, anabolic steroids, progestogens, and estrogens, each acting on specific receptors; nonsteroidal anti-inflammatory agents inhibit enzymes required for the prostaglandin cascade; penicillins and cephalosporins inhibit enzymes required to construct the bacterial cell wall; and tetracyclines act on bacterial ribosomes.

With the isolation and characterization of receptors becoming a common occurrence, it is hard to realize that the concept of receptors began as a postulate. It had been realized early that molecules with certain structural features would elucidate a specific biological response. Very slight changes in structure could cause significant changes in biological activity. These structural variations could increase or decrease activity or change an agonist into an antagonist. This early and fundamentally correct interpretation called for the drug (ligand) to fit onto some surface (the receptor) that had fairly strict structural requirements for proper binding of the drug. The initial receptor model was based on a rigid lock-and-key concept, with the drug (key) fitting into a receptor (lock). It has been used to explain why certain structural attributes produce a predictable pharmacological action. This model still is useful, although one must realize that both the drug and the receptor can have considerable flexibility. Molecular graphics, using programs that calculate the preferred conformations of drug and receptor, show that the receptor can undergo an adjustment in 3D structure when the drug makes contact. Using space-age language, the drug docks with the receptor.

More complex receptors now are being isolated, characterized, and cloned. The first receptors to be isolated and characterized were the reactive and regulatory sites on enzymes. Acetylcholinesterase, dihydrofolate reductase, an-giotensin, and human immunodeficiency virus (HIV) protease-converting enzyme are examples of enzymes whose active sites (the receptors) have been modeled. Most drug receptors probably are receptors for natural ligands used to regulate cellular biochemistry and function and to communicate between cells. Receptors include a relatively small region of a macromolecule, which may be an isolatable enzyme, a structural and functional component of a cell membrane, or a specific intracellular substance such as a protein or nucleic acid. Specific regions of these macromolecules are visualized as being oriented in space in a manner that permits their functional groups to interact with the complementary functional groups of the drug. This interaction initiates changes in structure and function of the macromolecule, which lead ultimately to the observable biological response. The concept of spatially oriented functional areas forming a receptor leads directly to specific structural requirements for functional groups of a drug, which must complement the receptor.

It now is possible to isolate membrane-bound receptors, although it still is difficult to elucidate their structural chemistry, because once separated from the cell membranes, these receptors may lose their native shape. This is because the membrane is required to hold the receptor in its correct tertiary structure. One method of receptor isolation is affinity chromatography. In this technique, a ligand, often an altered drug molecule known to combine with the receptor, is attached to a chromatographic support phase. A solution containing the desired receptor is passed over this column. The receptor will combine with the ligand. It is common to add a chemically reactive grouping to the drug, resulting in the receptor and drug covalently binding with each other. The drug-receptor complex is washed from the column and then characterized further.

A more recent technique uses recombinant DNA. The gene for the receptor is located and cloned. It is transferred into a bacterium, yeast, or animal, which then produces the receptor in large enough quantities to permit further study. Sometimes it is possible to determine the DNA sequence of the cloned gene. By using the genetic code for amino acids, the amino acid sequence of the protein component of the receptor can be determined, and the receptor then modeled, producing an estimated 3D shape. The model for the receptor becomes the template for designing new ligands. Genome mapping has greatly increased the information on receptors. Besides the human genome, the genetic composition of viruses, bacteria, fungi, and parasites has increased the possible sites for drugs to act. The new field of pro-teomics studies the proteins produced by structural genes.

The earlier discussion in this chapter emphasizes that the cell membrane is a highly organized, dynamic structure that interacts with small molecules in specific ways; its focus is on the lipid bilayer component of this complex structure. The receptor components of the membranes appear to be mainly protein. They constitute a highly organized, intertwined region of the cell membrane. The same type of molecular specificity seen in such proteins as enzymes and antibodies is also a property of drug receptors. The nature of the amide link in proteins provides a unique opportunity for the formation of multiple internal hydrogen bonds, as well as internal formation of hydrophobic, van der Waals, and ionic bonds by side chain groups, leading to such organized structures as the a-helix, which contains about four amino acid residues for each turn of the helix. An organized protein structure would hold the amino acid side chains at relatively fixed positions in space and available for specific interactions with a small molecule.

Proteins can potentially adopt many different conformations in space without breaking their covalent amide linkages. They may shift from highly coiled structures to partially disorganized structures, with parts of the molecule existing in random chain or folded sheet structures, contingent on the environment. In the monolayer of a cell membrane, the interaction of a small foreign molecule with an organized protein may lead to a significant change in the structural and physical properties of the membrane. Such changes could well be the initiating events in the tissue or organ response to a drug, such as the ion-translocation effects produced by interaction of acetylcholine and the cholinergic receptor.

The large body of information now available on relationships between chemical structure and biological activity strongly supports the concept of flexible receptors. The fit of drugs onto or into macromolecules is rarely an all-or-none process as pictured by the earlier lock-and-key concept of a receptor. Rather, the binding or partial insertion of groups of moderate size onto or into a macromolecular pouch appears to be a continuous process, at least over a limited range, as indicated by the frequently occurring regular increase and decrease in biological activity as one ascends a homologous series of drugs. A range of productive associations between drug and receptor may be pictured, which leads to agonist responses, such as those produced by cholinergic and adrenergic drugs. Similarly, strong associations may lead to unproductive changes in the configuration of the macromol-ecule, leading to an antagonistic or blocking response, such as that produced by anticholinergic agents and HIV protease inhibitors. Although the fundamental structural unit of the drug receptor is generally considered to be protein, it may be supplemented by its associations with other units, such as mucopolysaccharides and nucleic acids.

Humans (and mammals in general) are very complex organisms that have developed specialized organ systems. It is not surprising that receptors are not distributed equally throughout the body. It now is realized that, depending on the organ in which it is located, the same receptor class may behave differently. This can be advantageous by focusing drug therapy on a specific organ system, but it can also cause adverse drug responses because the drug is exerting two different responses based on the location of the receptors. An example is the selective estrogen receptor modulators (SERMs). They cannot be classified simply as agonists or antagonists. Rather, they can be considered variable agonists and antagonists. Their selectivity is very complex because it depends on the organ in which the receptor is located.

This complexity can be illustrated with tamoxifen and raloxifene (Fig. 2.2). Tamoxifen is used for estrogen-sensitive breast cancer and for reducing bone loss from osteoporosis. Unfortunately, prolonged treatment increases the risk of en-dometrial cancer because of the response from the uterine estrogen receptors. Thus, tamoxifen is an estrogen antagonist in the mammary gland and an agonist in the uterus and bone. In contrast, raloxifene does not appear to have much agonist property in the uterus but, like tamoxifen, is an antagonist in the breast and agonist in the bone.

Figure 2.2 • Selective SERMs.

Figure 2.3 • Examples of phosphodiesterase type 5 inhibitors.

There are a wide variety of phosphodiesterases throughout the body. These enzymes hydrolyze the cyclic phosphate esters of adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP). Although the substrates for this family of enzymes are cAMP and cGMP, there are differences in the active sites. Figure 2.3 illustrates three drugs used to treat erectile dysfunction (sildenafil, tadalafil, and vardenafil). These three take advantage of the differences in active site structural requirements between phosphodi-esterase type 5 and the other phosphodiesterases. They have an important role in maintaining a desired lifestyle: treatment of erectile dysfunction caused by various medical conditions. The drugs approved for this indication were discovered by accident. The goal was to develop a newer treatment of angina. The approach was to develop phosphodiesterase inhibitors that would prolong the activity of cGMP. The end result was drugs that were not effective inhibitors of the phosphodiesterase that would treat angina, but were effective inhibitors of the one found in the corpus cavernosum. The vasodilation in this organ results in penile erection.


One of the goals is to design drugs that will interact with receptors at specific tissues. There are several ways to do this, including (a) altering the molecule, which, in turn, can change the biodistribution; (b) searching for structures that show in creased specificity for the target receptor that will produce the desired pharmacological response while decreasing the affinity for undesired receptors that produce adverse responses; and (c) the still experimental approach of attaching the drug to a monoclonal antibody (see Chapter 5) that will bind to a specific tissue antigenic for the antibody. Biodistribution can be altered by changing the drug's solubility, enhancing its ability to resist being metabolized (usually in the liver), altering the formulation or physical characteristics of the drug, and changing the route of administration. If a drug molecule can be designed so that its binding to the desired receptor is enhanced relative to the undesired receptor and biodistribution remains favorable, smaller doses of the drug can be administered. This, in turn, reduces the amount of drug available for binding to those receptors responsible for its adverse effects.

The medicinal chemist is confronted with several challenges in designing a bioactive molecule. A good fit to a specific receptor is desirable, but the drug would normally be expected to dissociate from the receptor eventually. The specificity for the receptor would minimize side effects. The drug would be expected to clear the body within a reasonable time. Its rate of metabolic degradation should allow reasonable dosing schedules and, ideally, oral administration. Many times, the drug chosen for commercial sales has been selected from hundreds of compounds that have been screened. It usually is a compromise product that meets a medical need while demonstrating good patient acceptance.

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