DRUG RECEPTORS AND BIOLOGICAL RESPONSES
Although the term receptor is convenient, one should never lose sight of the fact that receptors are in actuality molecular substances or macromolecules in tissues that combine chemically with the drug. Since most drugs have a considerable degree of selectivity in their actions, it follows that the receptors with which they interact must be equally unique. Thus, receptors will interact with only a limited number of structurally related or comple-mentary compounds.
The drug–receptor interaction can be better appreci-ated through a specific example. The end-plate region of a skeletal muscle fiber contains large numbers of recep-tors having a high affinity for the transmitter acetyl-choline. Each of these receptors, known as nicotinic re-ceptors, is an integral part of a channel in the postsynaptic membrane that controls the inward move-ment of sodium ions . At rest, the post-synaptic membrane is relatively impermeable to sodium. Stimulation of the nerve leading to the muscle results in the release of acetylcholine from the nerve fiber in the region of the end plate. The acetylcholine combines with the receptors and changes them so that channels are opened and sodium flows inward. The more acetyl-choline the end-plate region contains, the more recep-tors are occupied and the more channels are open.When the number of open channels reaches a critical value, sodium enters rapidly enough to disturb the ionic bal-ance of the membrane, resulting in local depolarization. The local depolarization (end-plate potential) triggers the activation of large numbers of voltage-dependent sodium channels, causing the conducted depolarization known as an action potential. The action potential leads to the release of calcium from intracellular binding sites. The calcium then interacts with the contractile proteins, resulting in shortening of the muscle cell. The sequence of events can be shown diagrammatically as follows:
Ach + receptor → NA+ influx → action potential → increased free Ca++ → contraction
where Ach = cetylcholine. The precise chain of events following drug–receptor interaction depends on the particular receptor and the particular type of cell. The important concept at this stage of the discussion is that specific receptive substances serve as triggers of cellular reactions.
If we consider the sequence of events by which acetylcholine brings about muscle contraction through receptors, we can easily appreciate that foreign chemi-cals (drugs) can be designed to interact with the same process. Thus, such a drug would mimic the actions of acetylcholine at the motor end plate; nicotine and car-bamylcholine are two drugs that have such an effect. Chemicals that interact with a receptor and thereby initi-ate a cellular reaction are termed agonists. Thus, acetyl-choline itself, as well as the drugs nicotine and car-bamylcholine, are agonists for the receptors in the skeletal muscle end plate.
On the other hand, if a chemical is somewhat less similar to acetylcholine, it may interact with the recep-tor but be unable to induce the exact molecular change necessary to allow the inward movement of sodium. In this instance the chemical does not cause contraction, but because it occupies the receptor site, it prevents the interaction of acetylcholine with its receptor. Such a drug is termed an antagonist. An example of such a compound is d-tubocurarine, an antagonist of acetyl-choline at the end-plate receptors. Since it competes with acetylcholine for its receptor and prevents acetyl-choline from producing its characteristic effects, admin-istration of d-tubocurarine results in muscle relaxation by interfering with acetylcholine’s ability to induce and maintain the contractile state of the muscle cells.
Historically, receptors have been identified through recognition of the relative selectivity by which certain exogenously administered drugs, neurotransmitters, or hormones exert their pharmacological effects. By apply-ing mathematical principles to dose–response relation-ships, it became possible to estimate dissociation con-stants for the interaction between specific receptors and individual agonists or antagonists. Subsequently, meth-ods were developed to measure the specific binding of radioactively labeled drugs to receptor sites in tissues and thereby determine not only the affinity of a drug for its receptor, but also the density of receptors per cell.
In recent years much has been learned about the chemical structure of certain receptors. The nicotinic re-ceptor on skeletal muscle, for example, is known to be composed of five subunits, each a glycoprotein weighing 40,000 to 65,000 daltons. These subunits are arranged as interacting helices that penetrate the cell membrane completely and surround a central pit that is a sodium ion channel. The binding sites for acetylcholine and other agonists that mimic it are on one of the subunits that project extracellularly from the cell membrane. The binding of an agonist to these sites changes the conformation of the glycoprotein so that the side chains move away from the center of the chan-nel, allowing sodium ions to enter the cell through the channel. The glycoproteins that make up the nicotinic receptor for acetylcholine serve as both the walls and the gate of the ion channel. This arrangement repre-sents one of the simpler mechanisms by which a recep-tor may be coupled to a biological response.