Most drugs1, including those derived from plants, interact with cells in a specific way to produce their effects. These cellular interactions may occur between the drug and molecular targets inside the cell or on the cell membrane. Typically the molecular targets are proteins, and the structure of the protein helps to attract the drug (or active compound in plants) to bind to it. Proteins are large complex molecules made up of one or more chains of amino acids. Some parts of the amino acids have either positive or negative charges that help to attract drugs or other compounds to bind through electrostatic forces. A helical type protein embedded in a cell membrane is shown in Figure 6.
Figure 6 The helical nature of a protein is shown within a cell membrane. Proteins are macromolecules made of chains of amino acids. Some amino acid residues have positive charges and some have negative charges.
The active compounds derived from plants usually mimic or block the effects of chemicals in the body that bind to these same cellular targets. Drugs do not produce effects on all tissues of the body; drugs act at some sites to produce biologic effects, yet at other sites, drugs may not produce any biologic response – it will depend on where the targets are located. The ability of drugs to produce a biological effect is dependent on its binding to protein targets such as enzymes2, receptors3, or transporters4. When a drug binds to an enzyme, receptor, or transporter, it triggers a sequence of cellular events that produces a specific function. All drug interactions require a degree of specificity – that is, the binding of a drug to an enzyme, receptor, or transporter requires the both the target and the drug to have a specific chemical shape and properties to produce a cellular effect.
Some examples of the interactions between drugs derived from plants and their protein targets are given here. The first is a drug-enzyme interaction. An enzyme is a protein that facilitates a biochemical reaction. An enzyme acts as a catalyst and it binds to one or more of the reactants called a substrate5 (often a drug) to produce a product. In general, enzymes and drugs combine in a reversible fashion (see below). Aspirin (acetylsalicylic acid) is one example of a drug that produces its effects by combining with an enzyme. The enzyme cyclooxygenase6 (or COX) helps in the synthesis of chemicals (called prostaglandins7) that cause pain. Aspirin binds to the COX and in this case prevents the enzyme from helping generate the pain-producing chemicals. The COX is also present in the hypothalamus, an area of the brain that controls body temperature and appetite (among other things!). When aspirin reaches the hypothalamus, it prevents the synthesis of prostaglandins there, too, reducing a fever. Cyclooxygenase helps generate prostaglandins in the stomach to protect it against too much acid. Some people have stomach upset or even stomach bleeding (or ulcers) when they take aspirin because it has prevented the COX enzyme from generating the protective chemicals there.
Enzymes are also important in the body because they convert active drugs into inactive compounds or other active compounds (this usually occurs in liver cells). For example, enzymes help to convert aspirin into salicylic acid by hydrolysis8, which results in the aspirin molecule being cleaved by the addition of a water molecule (see Module 4 about hydrolysis). Salicylic acid also has analgesic activity, but it is more toxic than aspirin. Luckily, it doesn’t stay around in the body very long because it undergoes a reaction with another enzyme that helps convert it into an inactive compound or a metabolite9, which is excreted into the urine. Other examples of drugs metabolized by enzymes to produce active metabolites include heroin and codeine. Both of these opioid compounds are metabolized by enzymes to morphine, which produces analgesia, euphoria, and sedation. However, in the case of codeine, there is only a small amount of morphine generated – enough for analgesia and a bit of sedation, but not enough to cause euphoria. Whenever morphine is produced, it is then metabolized by additional enzymes to inactive compounds for excretion.
A second type of drug interaction is with a receptor. Nicotine and THC are examples of drugs that produce biological effects by binding with receptors. Nicotine binds to nicotinic acetylcholine10 receptors and THC binds to cannabinoid receptors. As with enzymes, a receptor is a specialized protein that can be present on the cell membrane, in the cytoplasm (see Module 6) or on membranes of cytoplasmic organelles. Drug-receptor interactions require a great degree of specificity to produce a biologic effect – much like a specific key that fits a lock. For example, nicotine binds to acetylcholine receptors of the nicotinic type in the central nervous system (i.e., the brain and spinal cord) (Figure 7). At the cellular level, the nicotine increases electrical currents to flow across the membrane, leading to increased electrical impulses along the neuron or muscle cell.
Figure 7 Watch how nicotine binds to the acetylcholine receptor, triggering the influx of Na+ into a receiving cell-either a nerve or muscle cell. From: Animated Neuroscience & the Actions of Nicotine, Cocaine and Marijuana in the Brain (Gross de Nunez & Schwartz-Bloom).
The location of acetylcholine receptors dictates the type of effect that is produced when nicotine binds to them. When nicotine binds to its receptors in the forebrain (in a small area called the nucleus accumbens11, a brain area associated with reward), it causes pleasure and is positively rewarding (i.e., the user wants to use it again). The binding of nicotine to receptors in the hypothalamus, decreases appetite. In contrast, when nicotine binds to receptors in the brainstem, which is responsible for basic physiological functions, it can cause nausea and vomiting during the early stages of smoking. High concentrations of nicotine can affect brainstem structures responsible for respiration, causing respiratory arrest. Acetylcholine receptors are also present outside the central nervous system, on muscles and on nerves that connect with blood vessels and the heart. When nicotine binds to these peripheral receptors on muscles, it makes them contract. When binding to receptors near the blood vessels and the heart, nicotine can increase the blood pressure and heart rate. This is the basis for heart disease in smokers. For a similar discussion of the effects of acetylcholine binding to its receptors (only some are nicotinic by the way), see Module 4.
THC exerts its effects by binding to specific receptors as well. These “cannabinoid” receptors respond to a chemical naturally found in the body called anandamide. Scientists are still studying what anandamide actually does in the body, and it appears to be important in producing some analgesia, increasing appetite, and reducing vomiting. (Recent studies indicate anandamide may also regulate memory!) The receptors for anandamide12 and for THC have been found in several areas of the brain, including the limbic system, a region of the brain that regulates mood, the cerebral cortex, a large outer region of the brain that is a target for the psychoactive13 effects of marijuana, the hypothalamus, important in regulating appetite, and the hippocampus, which is important in learning and memory. THC acts in these areas to elevate mood, cause perceptual distortions, increase appetite, and impair short-term memory (this is especially important because it disrupts learning). However, THC has very low toxicity, defined as its ability to produce death, because few cannabinoid receptors are present in brainstem areas that control respiration.
The third example of drug interactions is with transporters. Unlike nicotine and THC, which bind to receptors, cocaine acts by binding to plasma membrane transporters. These proteins transport the neurotransmitters dopamine14, norepinephrine15, and serotonin16 into nerve terminals after their release into the synaptic space Figure 8 demonstrates dopamine binding to its receptor and transporter.
Figure 8 Top: Watch dopamine bind to its receptor (in pink). Bottom: After dopamine comes off its receptor it is removed from the synaptic space by dopamine transporters (green), which transport it back into the terminal from which it was released. From: Animated Neuroscience & the Actions of Nicotine, Cocaine and Marijuana in the Brain (Gross de Nunez & Schwartz-Bloom).
Cocaine binds to the dopamine (and norepinephrine) transporters and blocks the transport of dopamine and norepinephrine back into the neuron (Figure 9). Thus, there is more dopamine or norepinephrine in the synaptic space, producing greater biologic effects. Similar to nicotine, the effects of cocaine depend on the type and location of the transporter to which the drug binds. Some dopamine transporters are located in the same forebrain area as the nicotine receptors – the nucleus accumbens. When cocaine prevents these transporters from working, the pleasurable effects of cocaine are produced. When cocaine prevents norepinephrine and dopamine transporters from working in the hypothalamus, it reduces the appetite. Norepinephrine transporters are located in nerves that connect with blood vessels and the heart. Block of these transporters results in more norepinephrine to bind to its targets, causing a sharp rise in blood pressure and heart rate.
Figure 9 Watch cocaine (larger blue objects) bind to dopamine transporters to block dopamine reuptake into the neuron. From: Animated Neuroscience & the Actions of Nicotine, Cocaine and Marijuana in the Brain (Gross de Nunez & Schwartz-Bloom).
1 a substance that affects the structure or function of a cell or organism.
2 a protein that catalyzes the rate at which a reaction occurs. It binds to one of the reactants (a substrate) to cause a change in the reactant’s structure, facilitating the reaction.
3 a protein to which hormones, neurotransmitters and drugs bind. They are usually located on cell membranes and elicit a function once bound.
4 a protein that usually exists within a membrane to transport a compound (either large or charged) across the membrane to the other side.
5 a molecule to which an enzyme binds.
6 an enzyme responsible for the oxidation of fatty acids to form prostaglandins (chemical compounds that have numerous effects in many tissues). It’s action is inhibited by aspirin.
7 a family of lipid (fat)-based hormones that are involved in several aspects of reproductive function, cardiovascular function, smooth muscle contraction and pain. They are generated by the oxidation of fatty acids with the help of cyclooxygenase.
8 a chemical reaction that involves the cleavage of a molecule in the presence of water. Water donates a H atom to one side of the broken bond and an OH molecule to the other side of the broken bond, forming 2 products. In the case of an ester, hydrolysis produces an alcohol and an acid.
9 usually an inactive form of a drug or other substance that is more polar (charged) than the parent compound. Drugs are metabolized by enzymes primarily in the liver.
10 a neurotransmitter stored in vesicles of nerve terminals; it is found in neurons within the central nervous system, the somatic nervous system, the parasympathetic nervous system and the sympathetic nervous system.
11 an area of the forebrain that is important in the rewarding or pleasurable effects of drugs.
12 a chemical produced by the body that has properties similar to THC from the marijuana (cannabis) plant.
13 pertains to drugs that act in the brain to produce changes in mood, perceptions and behavior.
14 a neurotransmitter stored in vesicles of dopamine nerve terminals; dopamine is contained in neuron pathways important in brain stimulation, addiction and control of movement. Its action is terminated by transporters to return it to the nerve terminal
15 a neurotransmitter in the catecholamine family that medicates chemical communication in the sympathetic nervous system. It is responsible for the physiologic response to a stressful challenge (the ‘flight or fight’ response). Norepinephrine action is terminated by transporters, like dopamine.
16 a neurotransmitter that is important in mood, perception, and eating behaviors. Its action is terminated by transporters, like dopamine.