Pharmacodynamics: Receptors and Concentration-Response Relationships

SITES OF DRUG ACTION

For most drugs, the site of action is a specific macromolecule, generally termed a receptor or a drug target, which may be a membrane protein, a cytoplasmic or extracellular enzyme, or a nucleic acid. A drug may show organ or tissue selectivity as a consequence of selective tissue expression of the drug target. For example, the action of the proton pump inhibitor esomeprazole occurs specifically in the parietal cells that line the gastric pits of the stomach because that is where its target, the potassium/hydrogen adenosine triphosphatase (K⁺/H⁺-ATPase), is expressed. Although the actions of a few drug types, such as osmotic diuretics (see Chapter 21), may not involve receptors as they are usually defined, the concept of receptors as sites of drug action is critical to understanding pharmacology.

Receptors (i.e., drug targets) fall into many classes, but two types predominate:

The former molecules could be considered generalized and the latter specialized receptors. Generalized receptors can include biological molecules with any function, including enzymes, lipids, or nucleic acids. The earlier example of the parietal cell K⁺/H⁺-ATPase is an example of this type of drug target. Specialized receptors include molecules like ion channels and proteins in the plasma membrane, designed to detect chemical signals and initiate a cellular response via activation of signal transduction pathways. The biological function of these molecules is to respond to neurotransmitters, hormones, cytokines, and autocoids and convey information to the cell, resulting in an altered cellular response. These types of receptors are the primary targets of most drugs in clinical use.

The concept of receptors was first proposed more than a century ago by the German chemist Paul Ehrlich, who was trying to develop specific drugs to treat parasitic infections. He proposed the idea of specific “side chains” on cells that would interact with a drug, based on mutually complementary structures. Each cell would have particular characteristics to recognize particular molecules. He proposed that a drug binds to a receptor much like a key fits into a lock.

This lock and key hypothesis is still relevant to how we understand receptors today. It emphasizes the idea that the drug and receptor must be structurally complementary to recognize each other and initiate an effect.

The specificity of such interaction raises the concept of molecular recognition. Drug receptors or targets must have molecular domains that are spatially and energetically favorable for binding specific drug molecules. It is not surprising that most receptors are proteins, because proteins undergo folding to form three-dimensional structures that could easily be envisioned to complement the structures of drug molecules. Enzymes are also reasonably common drug targets, although they fall under the generalized receptor class discussed.

The vast majority of drugs are small molecules with molecular weights below 500 to 800. These molecules interact with their protein targets via a number of different chemical bonds. The principal types of chemical bonds are depicted in Figure 1-1. These bonds apply to the interactions between drugs and classical receptors. Covalent bonds require considerable energy to break and are classified as irreversible when formed in drug-receptor complexes. Ionic bonds are also strong but may be reversed by a change in pH. Most drug-receptor interactions involve multiple weak bonds.

FIGURE 1–1 Types of chemical bonds and attractive forces between molecules that are pertinent to the interaction of drugs with their active sites.

AGONISTS AND ANTAGONISTS

Molecules that bind to receptors may have two major effects on the conformation of the receptor molecule. Agonists will bind to the receptor and activate it, like a key will fit into a lock and turn it. Activation of the receptor by agonist binding initiates a conformational change in the receptor and activation of one or more downstream signaling pathways. An example of the action of an agonist is provided by the effect of acetylcholine on the nicotinic cholinergic receptor at the neuromuscular junction. When acetylcholine binds to its binding sites on the external surface of this receptor, the channel opens and allows Na⁺ to flow down its electrochemical gradient and depolarize the muscle cell.

Antagonists are drugs that bind to the receptor but do not have the unique structural features necessary to activate it. In the lock and key analogy, antagonists can fit in the lock but cannot open it. Like agonists, antagonists fit into a specific binding site within the receptor but lack the proper structural features to initiate a conformational change leading to receptor activation. However, because they occupy the binding site of the receptor, antagonists inhibit activation by agonists. An example of antagonists is the class of neuromuscular blocking drugs used in the operating room to relax skeletal muscles during surgery. These drugs are analogs of curare, the active molecule in plant extracts used as arrow poisons by Native South Americans and studied by early European explorers. Curare is an antagonist at nicotinic cholinergic receptors at the neuromuscular junction and blocks the ability of acetylcholine or similar agonists to activate this receptor. This blockade inhibits muscle depolarization and causes paralysis of skeletal muscle, including the diaphragm and intercostal muscles needed for respiration. Several modern analogs of curare are available and used routinely during general anesthesia for relaxing muscle tone in patients undergoing surgery (see Chapter 12).

A third class of drugs that interact with receptors are allosteric modulators. These compounds bind to a site on the receptor distinct from that which normally binds agonist, called an allosteric site. Occupation of this site can either increase or decrease the response to the natural agonist, depending on whether it is a positive or negative modulator. Because allosteric modulators bind to sites different from where agonists bind, interactions between agonists and allosteric modulators are not competitive. The binding sites for agonists, antagonists, and allosteric modulators are depicted in Figure 1-2.

FIGURE 1–2 Major features of receptors depicting binding sites for agonists, antagonist, and allosteric modulators. Receptors embedded in cell membranes generally extend further on both the extracellular and intracellular sides. Attached to these proteins on the extracellular side are carbohydrate (glycosylation) chains. Shown are binding sites on the extracellular side for binding two molecules of an endogenous transmitter (dark blue symbols) to activate the transmembrane receptor. Agonists and antagonists compete with the endogenous transmitter for binding sites. Allosteric agonists (activators) or antagonists enhance or block the signal, respectively, by binding to allosteric sites that influence (wavy line) signal transmission. Other drugs can block signal transmission within the membrane or at intracellular signal reception points. The arrows indicate the direction of communication to the other side of the membrane.

RECEPTORS

Receptors are a primary focus for investigating the mechanisms by which drugs act. With the sequencing of the human genome, the structures and varieties of most receptors have now been identified. This advance has revealed many new receptors that could be potential drug targets for further pharmaceutical development. The major features of receptors are listed in Box 1-1. Three major concepts are illuminated by the concept of drug receptors.

The first is the quantitative relationship between drug concentration and the subsequent physiological response. This response is determined primarily by the affinity of the drug for the receptor, which is a measure of the binding constant of the drug for the receptor protein. A high affinity means that a low concentration of drug is needed to occupy receptor sites, whereas a low affinity means that much higher concentrations of drug are needed. The concentration-response curve is also influenced by the number of receptors available for binding. In general, more receptors can produce a greater response, although this is not always the case.

The second key concept is that receptors and their distribution in the tissues of the body are responsible for the specificity of drug action. The size, shape, and charge of a receptor determine its affinity for binding any of the vast array of chemically different hormones, neurotransmitters, or drug molecules it may encounter. If the structure of the drug changes even slightly, the type of receptor the drug binds to will also often change. Drug binding to receptors often exhibits stereoselectivity, in which stereoisomers of a drug that are chemically identical, but have different orientations around a single bond, can have very different affinities. For example, the L-isomer of narcotic analgesics is approximately 1000 times more potent than the D-isomer, which is essentially inactive for pain relief (see Chapter 36). The presence or absence of a single hydroxyl group, methyl group, or other apparently minor structural change can also dramatically alter the affinity of a drug for a receptor.

Receptors also explain the key concept of pharmacological antagonists, which prevent agonist activation by binding to a receptor. Administration of an antagonist will block tonic or stimulated activity of endogenous neurotransmitters and hormones, thus interfering with their normal physiological functions. An example is propranolol, which, by antagonizing β₁ adrenergic receptors, prevents the normal increase in heart rate associated with activation of the sympathetic nervous system (see Chapter 11).

Specialized receptors are usually involved in the normal regulation of cell function by hormones, neurotransmitters, growth factors, steroids, and autocoids. Although they are often found on the cell surface, where they are easily accessible to hydrophilic messengers, many hormone receptors are located inside the cell, and ligands for these molecules easily cross the cell membrane (see Part V). An example of an intracellular receptor is the glucocorticoid receptor (see Chapter 39). For most receptor types, multiple distinct subtypes can cause similar or distinct responses. This diversity of receptors and responses provides new targets for drug development.

LIGAND-RECEPTOR INTERACTIONS

In most cases, a drug (D) binds to a receptor (R) in a reversible bimolecular reaction described as:

(1-1)

Occupancy of the receptor by the drug may or may not alter its conformation. Antagonists participate only in the first equilibrium as they bind to the receptor and occupy the binding site. Agonists, on the other hand, have the appropriate structural features to force the bound receptor into an active conformation (DR*). Therefore agonists participate in both equilibria, binding to the receptor and initiating a conformational change. This conformational change leads to a series of events causing a cellular response. It is important to remember that the DR complex is usually reversible for both agonists and antagonists.

RECEPTOR SUPERFAMILIES

Four major superfamilies of receptors are involved in signal transduction, representing the targets of clinically useful drugs. These include ligand-gated ion channels (LGICs), G-protein–coupled receptors (GPCRs), receptor tyrosine kinase (RTKs), and nuclear hormone receptors. Table 1-1 contains a list of receptors in these classes that are important in the actions of several therapeutically useful drugs.

TABLE 1–1 Examples of Specialized Receptors

ACTH, Adrenocorticotrophic hormone; EGF, epidermal growth factor; Epi, epinephrine; NGF, nerve growth factor; NE, norepinephrine.

LGICs are most important in the central and peripheral nervous systems, excitable tissues such as the heart, and the neuromuscular junction. They include nicotinic cholinergic receptors (Fig. 1-3) at the neuromuscular junction, many of the γ-aminobutyric acid (GABA) and glutamate receptors in the brain, and one type of serotonin receptor. These receptors are responsible for fast synaptic transmission, where release of a transmitter causes an electrical effect on the postsynaptic neuron by opening a specific ion channel and leading to a change in membrane potential. LGICs are complex proteins composed of four or five subunits, and the specific subunit combinations differ at different sites in the body, allowing for selectivity of effects.

FIGURE 1–3 Crystal structure of the nicotinic cholinergic receptor. Binding sites for acetylcholine are shown as asterisks, with the gating portions shown with arrows.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

From Unwin N. The Croonian Lecture 2000. Nicotinic acetylcholine receptor and the structural basis of fast synaptic transmission. Philos Trans R Soc Lond B Biol Sci 2000;355:1813–1829.

For example, the subunits of the nicotinic receptor at the neuromuscular junction differ from those of the nicotinic receptor at autonomic ganglia. As a consequence, although the responses to acetylcholine and ion gating properties of these two channels are similar, these receptors are activated and antagonized by different drugs. This property allows selective blockade of the neuromuscular junction by drugs that do not block the channel at autonomic ganglia (see Chapter 12). Typically, LGICs have two binding sites for agonist and binding sites for allosteric modulators, which increase or decrease the ability of the transmitter to open the channel. One important class of allosteric modulators is the benzodiazepines, which are used extensively for the treatment of anxiety and sleep disorders (see Chapter 31). These drugs bind to γ-aminobutyric acid type A (GABA_A) receptors, which are ligand-gated chloride ion channels that are activated by the inhibitory neurotransmitter GABA. Benzodiazepines have no effect on channel opening by themselves, but their binding dramatically increases the ability of GABA to open the channel.

GPCRs are probably the most important class of receptors in pharmacology, because most currently marketed drugs target this receptor superfamily. GPCRs are much simpler than ligand-gated ion channels, being usually composed of a single subunit that contains seven transmembrane spanning domains. They are thought to have a single binding site, and as yet, there are only a few allosteric modulators for this class of receptors. GPCRs activate signals by inducing a conformational change that activates a large family of G-proteins to regulate signaling pathways (Fig. 1-4). These events regulate a host of important cellular functions (Box 1-2). GPCRs represent the largest protein family in the human genome, accounting for approximately 2% of all human genes. Approximately half of these receptors are olfactory receptors for detecting odorants; most of the remaining GPCRs respond to neurotransmitters, hormones, autocoids, and cytokines.

FIGURE 1–4 Structure of GPCRs and signaling molecules involved in regulation of adenylyl cyclase. Binding of the ligand to the stimulatory receptor (left)

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